Inflammatory Bowel Disease: A Practical Approach, Series #101

Clostridium Difficile Infection in Inflammatory Bowel Disease An Updated Review

June 2017 • Volume XLI, Issue 6
Andrew A. Nguyen,Angelica Nocerino,Dana J. Lukin,Arun Swaminath

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The incidence and severity of Clostridium difficile infection (CDI) is rising, primarily due to a new and virulent strain. Unlike patients in the general population, those with IBD who acquire C. difficile tend to be younger, have less antibiotic exposure and have more community-acquired infections. Given the high burden of CDI in IBD patients who have an acute IBD flare, all patients should be tested for CDI. Treatment of CDI focuses on antibiotics, however, in IBD patients, attention is required regarding immunosuppression during treatment. The aim of this paper is to review the most updated information on CDI in IBD including the epidemiology, pathogenesis, clinical presentation, risk factors, diagnosis and treatment guidelines.

The incidence and severity of Clostridium difficile infection (CDI) is rising, primarily due to a new and virulent strain. The impact of CDI on patients with inflammatory bowel disease (IBD) should not go unrecognized since this is a high risk patient population. Unlike patients in the general population, those with IBD who acquire C. difficile tend to be younger, have less antibiotic exposure and have more community-acquired infections. The clinical presentation of CDI in IBD is also unique compared to the general population. Given the high burden of CDI in IBD patients who have an acute IBD flare, all patients should be tested for CDI. Treatment of CDI focuses on antibiotics, however, in IBD patients, attention is required regarding immunosuppression during treatment. The aim of this paper is to review the most updated information on CDI in IBD including the epidemiology, pathogenesis, clinical presentation, risk factors, diagnosis and treatment guidelines.

Andrew A. Nguyen, DO1 Angelica Nocerino, MD1 Dana J. Lukin, MD, PhD2 Arun Swaminath, MD3 1Resident, Department of Internal Medicine, Lenox Hill Hospital, Hofstra Northwell School of Medicine, New York, NY 2Assistant Professor, Department of Gastroenterology and Liver Diseases, Montefiore Medical Center, Albert Einstein College, Bronx, NY 3Associate Professor, Department of Gastroenterology, Lenox Hill Hospital, Hofstra Northwell School of Medicine, New York, NY

INTRODUCTION

Clostridium difficile (C. difficile) is an obligate, anaerobic, gram-positive, spore-forming bacillus that is associated with pseudomembranous colitis and the clinical spectrum ranges from asymptomatic carriage to severe colitis, sepsis and death.1 In the United States (US), it is becoming an increasing health concern as its incidence is on the rise. C. difficile recently surpassed methicillin resistant Staphylococcus aureus (MRSA) as the most common hospital acquired infection in the US.2 In addition, in 2014, deaths from CDI were greater than those associated with HIV infection.3 CDI is higher amongst females, whites and the elderly; however, CDI in IBD patients is also increasing.4,5

In IBD patients, CDI may be more prevalent in ulcerative colitis (UC) than Crohn’s disease (CD).6 Patients with IBD complicated by CDI have higher mortality and resource utilization, including increased hospitalization, longer length of stay and higher inpatient morbidity.7-10 In addition, CDI complicating IBD may lead to an increase in the need for surgical intervention. 8 Thus, it is important to evaluate CDI and its role in the IBD community.

Epidemiology of CDI

CDI is a major cause of morbidity and mortality worldwide and in the US in particular. In 1978, C. difficile was first recognized as a major cause of antibiotic related colitis. Since then the incidence and severity of CDI has increased with a particular rise in the past decade. From 2000 to 2006, the number of hospitalizations secondary to CDI nearly doubled in the general population in the US, with a reported annual incidence of 300,000 hospitalizations and an annual healthcare cost of 4.8 billion dollars.11,12 In 2011, there were over 450,000 cases of CDI, resulting in approximately 30,000 deaths.13 The incidence of hospitalizations, however, minimizes the true prevalence of CDI, as community acquired infections are also on the rise and account for nearly 27% of all C. difficile related infections.14

The emergence of a highly virulent C. difficile strain (BI/NAP1/027) serves as a predictor of disease severity and risk of mortality.15 This strain, which is group B1 (restriction-endonuclease analysis), type NAP1 (North American PFGE type 1) and ribotype 027 (polymerase chain reaction), is resistant to fluoroquinolones and has been shown to produce larger amounts of toxin than other C. difficile strains.14,16 This is due to a mutation of the regulatory tcdC gene and the production of C. difficile transferase, an ADP-ribosylating binary toxin.17 One in vivo study compared a reference C. difficile strain in mice to the B1/NAP1/027 strain and found that the B1/NAP1/027 strain has at least 11 different antigenic epitopes compared to the reference strain, with less susceptibility to antibody neutralizations. Furthermore, it exhibits a lower dose needed for virulence compared to the reference strain.18

Patients with IBD have an increased risk and higher incidence of CDI compared to the general population.5,19 In a retrospective analysis of nationwide inpatient admissions for CDI in those with IBD, CDI prevalence in the general population had an incidence of 4.5 per 1000. CDI was higher among those with UC (37.3 per 1000) and CD (10.9 per 1000).6 A second population study examined the rate of hospitalizations of IBD patients in the US and discovered a similar incidence of CDI, with a rate of 2.8% in UC and 1% in CD.19 Compared to patients with CD and CDI, those with UC and CDI also had higher rates of surgery (10.4% vs. 8%), and higher mortality rates (5% vs. 3%).20 Two recent meta-analyses confirm higher rates of both colectomy and mortality in IBD patients with CDI with a more significant effect in UC.21,22 Although the reason for the increase in incidence of CDI and disease severity among those with UC as compared to CD remains unclear, it is hypothesized that colonic involvement, seen more frequently in patients with UC, may be an attributable risk factor.10 Interestingly, there was a geographical variation of CDI, with more hospitalizations and higher mortality rates seen in the Northeast region of the US as compared to the Southwest region.23 The prevalence of asymptomatic and community acquired CDI among the IBD population is also on the rise. Clayton et al. compared 122 individuals with IBD to 99 individuals without IBD and discovered that 8.2% of the IBD population is colonized with C. difficile, as compared to 1% of the general population.24

CDI appears to have a more aggressive disease course in IBD patients. Ananthakrishnan et al. examined 124,570 hospitalizations among those with CDI and IBD, CDI alone and IBD alone. Patients with IBD and CDI had greater mortality (4.2%) than those with CDI alone (3.7%) or IBD alone (0.5%).20 Furthermore, the length of hospital stay was longer in the those with CDI and IBD (7 days) as compared to CDI alone (5 days) and IBD alone (4 days).20 Those with IBD are also more likely to suffer from CDI recurrence, with rates as high as 40% as compared to only 20% of those without IBD.25 Up to 35% of UC patients had a colectomy one year after diagnosis of CDI, as compared to 9.9% in those without IBD.26

Pathogenesis

C. difficile can be transmitted via fecal-oral route by ingestion of spores. It is easily spread, as it can persist on fomites for several months. Both toxin and non-toxin strains exist though only the toxic strains are associated with disease.27 Most C. difficile strains produce toxin A and toxin B, which are products of tcdA and tcdB genes. Strains producing one or both toxins are able to cause disease, while strains producing both toxins are the most virulent.17 Toxin A, an enterotoxin, binds to intestinal epithelial cells, subsequently damaging intestinal villous tips and the tight junctions between the epithelial cells.18 Toxin B, a cytotoxin, plays a role in promoting neutrophil chemotaxis, and the activation of the cytokine cascade, including tumor necrosis factor (TNF), interleukin (IL)-6, IL IL-8, IL-1Β, leukotrienes B4 and interferon-y. This creates a pro-inflammatory state in the mucosa of the intestine, leading to diarrhea, ulceration and the formation of pseudomembranes.28

The natural gut microbiota plays a major role in the defense against CDI, as it stimulates the mucosal immune system and aids in the transformation of secondary bile acids known to inhibit C. difficile germination.30 Distinct changes within the intestinal microbiome have been associated with CDI, including increases in the relative abundance of Proteobacteraciae and Verrucomicrobiota with corresponding decreases in Enterococcaceae, Leuconostocacaea, Prevotellaceae and Spirochaetaceae.31 A decrease in endogenous gut diversity can, therefore, weaken barrier defenses and predispose to CDI. Although the etiology of IBD is unknown, it is theorized that environmental factors and genetics trigger an immune response against the natural bowel flora.32 Subsequently, this leads to chronic inflammation of the intestinal mucosa and a decrease in microbiota diversity.33 It is well known that the ileum plays a major role in the active reabsorption of bile acids, which has a role in inhibiting C. difficile germination. In patients whose terminal ileum is affected by Crohn’s disease, the chronic inflammation can result in the destruction of the sodium/bile acid co-transporting polypeptides located on the ileal enterocytes, which subsequently results in malabsorption of bile acids, and may predispose to CDI.27,34 Genetics may also play a role. Polymorphisms in the IL-4 receptor gene and TNF receptor superfamily member 14 can be associated with IBD and may also increase susceptibility to CDI.35,36 These factors may explain the increased risk of CDI in those with IBD.

Presentation

Clinically, C. difficile has a wide range of expression, from asymptomatic carrier to toxic megacolon and colonic perforation. Typical diarrhea, nausea, vomiting, abdominal pain, fever and leukocytosis characterize CDI. CDI can mimic IBD flares often making it difficult for physicians to distinguish the two, and thus it is always recommended that all patients with IBD who present with a flare be tested for CDI. CDI might present as bloody diarrhea in IBD patients, which may not be commonly seen in the general population, affected by C. difficile.

Post-operative IBD patients may be at higher risk of developing CDI than those without a surgical history. The risk can be seen as early as the first 90 days after surgery but can also occur years later.37,38 CDI may manifest as an increase in ileostomy output, and may present as pouchitis in those with an ileal pouch.39 CDI enteritis, a relatively rare entity, occurs almost exclusively in post-operative patients. Roughly half of cases occur in IBD patients and is associated with a high mortality rate.40 Thus the absence of a colon should not preclude the evaluation for CDI. Antibiotics prior to surgery have been shown to increase the risk of CDI.41 Furthermore, it is thought that those who develop CDI immediately post-operative may have had undiagnosed CDI of the colon prior to surgery that subsequently migrates to the small bowel. It has also been shown that the flora of the small bowel mimics colonic flora after colectomy increasing the risk of CDI.38

Endoscopically there exists a key difference between those with CDI and concomitant IBD and those with CDI alone. While pseudomembranes can be seen in up to 60% of those with CDI in the general population, pseudomembranes may not be as common in those with IBD. In a retrospective multi-center study performed in 20 centers in Europe and Israel by Ben-Horin et al, 93 IBD patients with a diagnosis of CDI underwent lower endoscopy. Endoscopic pseudomembranes were seen in only 13% of patients. In those patients who were found to have pseudomembranes, fever was also commonly present.42 In another retrospective study of 24 patients with IBD and CDI, pseudomembranes were not seen endoscopically or histologically in any of the patients.43 It is theorized that in IBD the colon is chronically damaged and cannot mount an adequate local inflammatory response to form pseudomembranes. Another hypothesis is that immunomodulators themselves affect the inflammatory cascade in a way that leads to an absence of pseudomembranes.29,44

RISK FACTORS

Traditionally, antibiotic use, in particular clindamycin, fluoroquinolones and broad-spectrum cephalosporin, is considered to be the most common risk factor for CDI. The loss of microbial diversity from antibiotic use creates an optimal environment that predisposes patients to CDI. In the general population CDI is the etiology in up to 55% of cases of antibiotic associated colitis.44,45 Other risk factors for CDI include older age, residence in long term care facilities, hospitalization, immunosuppression, chronic kidney disease, gastric acid suppression through proton pump inhibitor use, surgery of the gastrointestinal tract and malignancy.46

IBD patients constitute a unique risk group as they tend to be young individuals with a history of outpatient- acquired infections and overall less antibiotic exposure compared to the general population.44 Population studies have demonstrated that up to 40% of CDI in IBD had no prior antibiotic exposure and that 76% of cases were diagnosed in the outpatient setting.43,47 Multiple studies have also found that colonic involvement is an important risk factor for CDI in IBD.43,44 In one single center study, Issa et al. found that up to 91% of patients with IBD who were diagnosed with CDI had colonic involvement.43 A second population study demonstrated that those who had IBD with colonic involvement had a 3.5 times higher incidence of CDI compared to those whose inflammatory disease only affected the small bowel.6

CDI is also associated with high rates of colectomy and mortality amongst patients with IBD.21,22 Studies have shown an incidence of CDI ranging from 10 % to 18.3% in patients who underwent an ileal pouch-anal anastomosis.41,48 Ananthakrishnan et al. analyzed the occurrence colectomy and/or death within 180 days of CDI in a retrospective multi-institution database of IBD patients. Approximately 20 percent of patients met this endpoint at a median of 31 days and predictors of severe outcomes included albumin <3 g/dL (HR 2.97), hemoglobin <9 mg/dL (HR 2.51), age >65 (HR 2.14) and serum creatinine >1.5 g/dL.49

In comparison to the general population, use of proton pump inhibitor medications has been reported to be lower in IBD patients with CDI than in non-IBD patients with CDI.50 Furthermore, Ananthakrishnan et al. found that 25(OH)-Vitamin D levels differed significantly amongst IBD patients with and without CDI (20.4 vs. 27.1, respectively) and levels below 20 ng/mL were associated with an odds ratio of 2.27 for CDI.51

The use of immunomodulators is also an important risk factor that should be well recognized. Issa et al. reported that 78% of patients with IBD and CDI were on immunosuppressive medication, including azathioprine, 6-mercaptopurine, methotrexate and infliximab.43 Schneeweiss et al. analyzed 10,662 IBD patients and discovered that those on steroids were three times more likely to acquire CDI as compared to those on other immunosuppressant agents.52 In this study the use of infliximab did not increase risk of CDI, which is in contrast to the RECIDIVISM study, which discovered that infliximab, and not adalimumab, was associated with increased recurrence of CDI compared to adalimumab.50 Lastly, analysis of the Food And Drug Administration Adverse Events Reporting System showed an increased incidence of CDI amongst patients receiving therapy with vedolizumab, but not with anti-TNF biologics.53 Based on these studies, steroids appeared to increase the risk of CDI, but there have been inconsistent findings regarding the risk of biologics.

Diagnosis

Diagnosis of CDI in IBD patients is the same as the diagnosis in the general population. Multiple diagnostic modalities are available, including cell cytotoxicity assays, enzyme immunoassay (EIA) for toxin (tcdA and tcdB), culture, glutamate dehydrogenase (GDH) detection, nucleic acid amplification tests (NAAT) and multi-step algorithms. Regardless of the modality chosen, testing should only be performed on diarrheal stool as testing on formed stool can decrease the specificity of diagnosis confusing a carrier with an active infection.54 The gold standard for the diagnosis of CDI is stool culture for toxin which requires growing C. difficile and an additional step to detect the presence of toxin. This test is time and labor intensive, taking up to 48 hours for results.55 Thus, rapid testing is commonly preferred. One such test is GDH detection via EIA, however, GDH is present in both toxigenic and non- toxigenic strains, therefore, testing for GDH requires an additional modality that detects toxin. Due to the complexity and time sensitivity of CDI diagnosis, many have suggested multistep algorithms for rapid diagnosis.25,54,55 Multistep algorithms involve a two-step process, initially using a highly sensitive test to screen for CDI that is reflexively followed by a highly specific test to confirm the diagnosis. Detection of GDH has a high negative predictive value and is commonly used as the first step in many proposed multistep algorithms. One systematic review found that diagnosis with multistep algorithms using PCR for toxin or single step PCR on liquid stools may have the best outcome (multistep: sensitivity 0.68-1.00 and specificity 0.92- 1.00; single step: sensitivity 0.86-0.92 and specificity 0.94-0.97).56 Thus, EIA for GDH and toxin or PCR for tcdB gene seem to be the most commonly applied tests in clinical practice.

The American College of Gastroenterology guidelines recommend screening for CDI in IBD patients who are hospitalized for a flare and IBD patients who develop diarrhea when disease activity was previously in remission or have risk factors for CDI.57 Colonoscopy is not commonly used in the diagnosis of CDI in the general population, as there are other less invasive modalities available. However, in the IBD population, colonoscopy may be used more frequently as presentation of CDI and IBD can be similar but its value in differentiating the two may be limited. Nevertheless it is important to remember that the typical findings of pseudomembranes are not commonly found in IBD patients and the histologic findings may be difficult to differentiate from IBD.43 Computed tomography scans may aid in the diagnosis of CDI if typical features of CDI are present (i.e. nodular haustral thickening or the accordion pattern), however, this test is also limited by a lack of specificity.58

Treatment

Treatment of CDI is based on the severity of CDI, defined as mild to moderate (leukocytosis with white blood cell count <15,000 cells/µL and serum creatinine level <1.5 times the premorbid level), severe (leukocytosis with a white blood cell count of ≥15,000 cells/µL or a serum creatinine level ≥1.5 times the premorbid level, serum albumin <3 g/dL) or severe complicated (hypotension or shock, ileus, megacolon).54,57 In addition, whether the diagnosis is a primary event or a recurrence also determines the course of treatment.

There are three antibiotics that are recommended in the treatment of CDI among the general population, including metronidazole, vancomycin and fidaxomicin. Metronidazole is the drug of choice for mild to moderate CDI, whereas, vancomycin is preferred in severe CDI.54 Previous studies have shown that in severe and complicated CDI metronidazole has a higher rate of treatment failures.56 In addition, metronidazole may be inferior to vancomycin despite the severity of disease suggesting vancomycin should be the first choice in the treatment of CDI.59,60

Fidaxomicin is the most recently approved antibiotic for the treatment of primary and first recurrence CDI. It was introduced in 2011 when Louie et al. showed that the rates of cure with fidaxomicin were non-inferior to the rates of cure with vancomycin.61 In addition, fidaxomicin was associated with a significantly lower rate of recurrent CDI.62 Unfortunately, the use of fidaxomicin is limited by its high cost.6633

Fecal microbiota transplantation (FMT) has a role in CDI. FMT changes the bacterial composition of the gut microbiota, and has been associated with resolution of CDI symptoms.64 FMT is 70-91% effective in achieving cure after initial treatment and 89-98% effective in overall cure.65-67 Systematic reviews have found an 89.7%-92% cure rate of recurrent CDI after FMT.68,69 There are no randomized controlled trials assessing the role of FMT in primary non-recurrent CDI, however, Lagier et al. conducted an open label, nonrandomized, prospective study assessing early (within one week of infection) FMT via nasogastric infusion with fresh stool in primary CDI that showed a significant reduction in mortality.70 Unfortunately, the route (oral vs. endoscopic), stool preparation (fresh vs. frozen), amount of stool infusate and donor characteristics have not been standardized.

Monoclonal antibodies to C. difficile toxin are now available to decrease CDI recurrence when part of the initial treatment algorithm.71 There are two monoclonal antibodies that have been evaluated in the prevention of recurrent CDI, actoxumab and bezlotoxumab, which bind and neutralize C. difficile toxins A and B, respectively. Wilcox et al. conducted two multi- center randomized, double blind, placebo-controlled trials (MODIFY I and MODIFY II) with participants with either primary CDI or recurrent CDI who were treated with standard of care antibiotics (vancomycin, metronidazole or fidaxomicin) for 10-14 days. They found that the rate of recurrent CDI was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% vs. 28%; 95% CI -15.9 to -4.3; P<0.001; MODIFY II: 16% vs. 26%; 95% CI -15.5 to -4.3; P<0.001) and significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% vs. 28%; 95% CI -17.4 to -5.9; P<0.001; MODIFY II: 15% vs. 26%; 95% CI -16.4 to -5.1; P<0.001).72 The original MODIFY I trial included an actoxumab alone arm, however, this arm was discontinued after planned interim analysis did not show efficacy. The rates of recurrent infection were lower in both groups that received bezlotoxumab compared to the placebo group. Approximately, 20% of participants included in the study were immunocompromised, however, supplementary material do not distinguish the defining characteristics of those subjects. Bezlotoxumab’s role in the treatment of IBD patients with CDI is undefined.

Management of CDI in IBD

The management of CDI in IBD patients is difficult as the symptoms cannot be attributed to either IBD flare or CDI alone. Many patients with IBD are immunocompromised often due to treatment with immunomodulators or biologics making the choice of treatment difficult. In a non-IBD population hospitalized with CDI, use of corticosteroids within 2 weeks of diagnosis has been associated with a two-fold increase in mortality.73 De-escalation of corticosteroid dose may lessen the severity of an active CDI.43 Patients with IBD and a concomitant CDI treated with immunomodulators and antibiotics had poorer outcomes than those treated with antibiotics alone. This was based on 155 patients (antibiotics: n = 51 vs. antibiotics and immunomodulators: n =104).74 In contrast, Lukin et al. recently performed a multi-center retrospective cohort study of 157 patients with IBD and CDI that assessed immunosuppressive medications on the clinical outcome in this patient population. They found a marked increase in serious outcomes (i.e. death, sepsis, colectomy) among patients who did not have an escalation of IBD therapy within 90 days of CDI suggesting a subpopulation of IBD with CDI where CDI is a marker of disease severity.75 This concept is supported by the data from Ananthakrishnan et al, but goes further in suggesting that a specific subpopulation of patients with CDI and IBD could be harmed if IBD therapy is not escalated.10

No prospective studies have been performed to assess the antibiotic preference of CDI in IBD patients, however, as CDI in IBD is high risk and a complicated disease, it is reasonable to consider vancomycin as first line treatment in these patients.59 This group may also be ideal to benefit from toxin B antibody during initial treatment, though no studies in IBD patients have yet been performed.

There is a growing consensus that FMT may be used in the treatment of CDI in UC patients. A systematic review of 17 articles that assessed FMT in IBD found 15 IBD patients (8 UC and 7 CD) with CDI who were treated with FMT. There was outcome data for 12/15 with resolution of CDI when treated with FMT based on negative stool sample enterotoxin. However, only 11/12 patients had reduction or complete resolution of diarrhea.76 Another multicenter retrospective series that assessed FMT for CDI treatment in immunocompromised patients included 36 patients with IBD. In the IBD patients, they found resolution of CDI in 86% of patients after a single FMT and an overall cure rate of 94%.66 In a prospective study examining FMT for the treatment of refractory CDI by Hamilton et al., 14 of 43 study patients were reported to have UC.77 While no subgroup analysis is provided, all UC patients were reported to have improved from CDI after FMT. A more recent prospective study reported cure rates of 79% after first FMT and 90% overall in IBD patients undergoing FMT for CDI.78 In this study, treatment failure was associated with hypoalbuminemia. Additionally, the durability of FMT within IBD patients appears to be less than in the general population. In a small pediatric study in recurrent CDI, analysis of the fecal microbiome in patients both with and without IBD resembled that of the donor immediately following FMT but the microbiome in patients with IBD returned to a signature resembling that before FMT after 6 months.79 Lastly, the possibility of FMT-related adverse effects, including exacerbation of IBD, remains uncertain.66,80 Thus, there may be benefit in treatment of CDI in IBD patients with FMT; however, larger studies need to be performed to assess FMTs efficacy and potential adverse effects in IBD patients with CDI.

In 2013, the American College of Gastroenterology put forth guidelines for the management of C. difficile infection, which include recommendations for patients with IBD.57 These guidelines emphasize that CDI must be suspected in all IBD patients hospitalized for or presenting for outpatient evaluation of a presumed disease flare, including patients with ileal pouch following total proctocolectomy. While there is low- quality evidence currently available to guide IBD treatment at the time of CDI, these guidelines advocate for the simultaneous empiric treatment of CDI and IBD while awaiting the results of diagnostic testing. Maintenance of ongoing immunosuppressive therapy is recommended during active CDI, but escalation of therapy is advised only after appropriate treatment of the infection for 72 hours. Further, high quality prospective studies are needed to inform future treatment guidelines.

CONCLUSION

CDI is an increasing health concern due to the virulence of B1/NAP1/027 strain with prevalence increasing in both the hospital and community setting. CDI is particularly important in IBD patients as it complicates the disease course and increases morbidity and mortality. CDI in IBD can be difficult to diagnose as it can mimic or complicate IBD flares and does not classically present in the same manner as the general population, such as increased asymptomatic carriage and community acquired CDI and a decrease in frequency of pseudomembranes in the IBD population. All patients with IBD who have an acute flare of their disease should be tested for CDI. There are multiple antibiotics available in the treatment of CDI; however, oral vancomycin may be the preferred agent in IBD patients. FMT and monoclonal antibodies to toxin B are two newly proposed modalities to aid in the treatment of CDI, however, their role in CDI and IBD is currently unclear. Immunosuppression in IBD patients with CDI can also be difficult to manage, however, a recent study has shown that there may be a benefit to corticosteroids and biologics after antibiotic treatment for CDI. There is a developing body of information regarding CDI in IBD management, however, further studies are still required to establish a standard of care and management.

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A Case Report

An Uncommon Cause of Dysphagia in a 35 Year Old Male

May 2017 • Volume XLI, Issue 5
Carmelo Blanquicett,Terence Dunn,Arjun Nanda,Frederick Weber

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Typical causes of intermittent esophageal dysphagia in a young person include eosinophilic esophagitis, esophageal dysmotility and esophageal rings. We report a 35-year-old male with a one year history of intermittent dysphagia to solid foods. After the endoscopic removal of a food bolus, a barium swallow revealed extrinsic compression of the proximal esophagus. Computed tomography angiogram revealed an aberrant right subclavian artery (ARSA) coursing behind the esophagus, suggesting the diagnosis of dysphagia lusoria. Although rare, dysphagia lusoria represents an important consideration in the differential diagnosis of intermittent esophageal dysphagia in a young adult.

Carmelo Blanquicett, MD, PhD1 Terence Dunn, MD1 Arjun Nanda, MD,2 Frederick Weber, MD2 1Department of Internal Medicine, 2Dept of Gastroenterology and Hepatology, University of Alabama at Birmingham, AL

INTRODUCTION

In young adults, esophageal dysphagia is most commonly attributed to eosinophilic esophagitis, strictures, motility disorders or neurological injury. Occasionally symptoms can result from extrinsic compression from mediastinal masses, vascular structures or surgical changes. We present the case of a 35-year-old male who presented with complaints of intermittent esophageal dysphagia and was found to have dysphagia lusoria. Although uncommon, it is important to consider this diagnosis when evaluating patients with dysphagia.

CASE REPORT

A 35-year-old Caucasian male was admitted to our institution after he presented to the emergency department with the sensation of food stuck in his chest for two days following the consumption of pork. He reported a one-year history of intermittent solid- food dysphagia with episodes typically resolving by “?coughing up”? and regurgitating the food bolus. He denied choking, aspiration, associated dyspnea, difficulty initiating a swallow or odynophagia. He denied tiring upon chewing or focal weakness. His weight had been unchanged, and he denied any prior tobacco use. He underwent an esophagogastroduodenoscopy (EGD) with esophageal biopsies two months prior to presentation at an outside facility and was placed on empiric proton pump inhibitor (PPI) therapy without clinical benefit. Biopsies did not reveal evidence of eosinophils. His past medical history included chronic tension headaches but he denied a history of atopy or asthma.

At the time of our evaluation, he was handling his oral secretions and had no complaints of dyspnea or choking. His vital signs and physical examination, including a comprehensive cardiovascular and head, eyes, ears, nose and throat (HEENT) exam were unremarkable. Laboratory studies were within normal limits. After glucagon was administered in the emergency room without clinical improvement, a large food bolus was successfully removed endoscopically from the proximal esophagus. The underlying mucosa appeared friable but no strictures or rings were visualized.

Post-endoscopy esophagram revealed a smooth narrowing at the pharyngoesophageal junction consistent with a cricopharyngeal bar. More significantly, there was extrinsic compression of the proximal esophagus distally (Figure 1). A computed tomography (CT) angiography of the chest demonstrated an aberrant right subclavian artery (ARSA) passing posteriorly to the esophagus resulting in compression of the posterior aspect of the thoracic esophagus (Figure 2). These findings, in conjunction with the patient?s history, suggested the diagnosis of dysphagia lusoria. The patient was referred to vascular surgery clinic for consideration of surgical correction. A reconstruction of the CT images was performed as shown in Figure 3.

DISCUSSION

Dysphagia lusoria results from a congenital abnormality in the development of the aortic arch and its branches causing extrinsic compression of the esophagus. In the majority of cases, the causative vessel is an ARSA originating from a left-sided aortic arch, but persistent right-sided aortic arch with aberrant left subclavian artery has also been described.1 The ARSA originates from the proximal portion of the descending thoracic aorta with three possible anatomic positions: posterior to the esophagus (80%), between the esophagus and trachea (15%) and anterior to the trachea (5%).2 This abnormal course led to the term lusorian artery from the Latin lusus naturae or “?freak of nature”?. The prevalence of a lusorian artery has been estimated at 0.4% to 0.7% among the general population.1 Patients with Down Syndrome commonly have vascular anomalies, and the incidence of ARSA in these patients has be reported in up to 39%.3 Based on retrospective data, only 30-40% of individuals with ARSA develop symptoms of dysphagia in their lifetime.1 Without intervention, progressive worsening of symptoms may occur via proposed mechanisms such as age-related loss of esophageal or arterial compliance and aortic elongation. 2

Depending on the severity of the symptoms, the approach to management varies. In mild cases, behavioral modification strategies, including smaller bites with more thorough chewing, can be adopted.4 Adjunctive PPI therapy may also improve symptoms. In more severe cases, a surgical approach is warranted. Options include open surgical repair with ligation of the aberrant subclavian artery and anastomosis to the ipsilateral carotid artery or a combined surgical and endovascular (hybrid) approach using stenting as well as carotid-to-subclavian bypass grafting.5 High success rates, with complete resolution of symptoms, have been reported in patients who underwent surgery.5,6 We recommended our patient undergo surgical evaluation, given his history of recurrent dysphagia with impaction, in order to address the degree to which his symptoms had progressed.

In summary, dysphagia lusoria represents a rare clinical manifestation of a somewhat uncommon vascular anomaly and should be considered in the evaluation of intermittent esophageal dysphagia in a young adult.

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Dispatches From The Guild Conference, Series #4

Rheumatologic Complications of Inflammatory Bowel Diseases

May 2017 • Volume XLI, Issue 5
Arthur Kavanaugh,Abha Goyal Singh

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Beyond gastrointestinal symptoms and complications, IBD is a systemic disease that is frequently accompanied by extraintestinal manifestations (EIM) involving virtually every organ in the body. Rheumatologic extraintestinal manifestations and complications are common, presenting as peripheral arthritis and/or axial arthritis which can add to the detrimental impact that IBD has on affected patients in terms of pain, quality of life and functional status. Here we discuss the importance of a high index of suspicion and early treatment, which may decrease healthcare burden.

Rheumatologic manifestations are the most common extra-intestinal complications in patients with inflammatory bowel disease (IBD), and have been reported to occur among 6-46% of IBD patients. The immunopathophysiology may relate to aberrant lymphocyte trafficking from the inflamed gut into the articular synovium as well as extra-articular tissues, especially the entheses. There are multiple potential clinical presentations including peripheral arthritis, spinal or axial arthritis and enthesitis. Peripheral arthritis accompanied IBD may be oligo-articular or polyarticular, with the former occurring more early in the disease course, and sometimes transitioning to the latter. Much of data relevant to the treatment of peripheral arthritis related to IBD comes from the literature on the treatment of psoriatic arthritis (PsA) with peripheral arthritis. Treatment options include disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), sulfasalazine, leflunomide and apremilast. Among biologic agents, tumor necrosis factor inhibitors (TNFi) have the longest and largest clinical data supporting their substantial efficacy. The most relevant data concerning the treatment of spinal, also called axial, arthropathies comes from studies of patients with ankylosing spondylitis (AS). While non-steroidal anti-inflammatory agents (NSAIDs) and specific cyclooxygenase 2 (COX2) inhibitors are effective in both peripheral and axial arthritis, their use in IBD must take into account their potential effects on the bowel. While DMARDs are ineffective for axial arthritis, TNFi are highly effective. IL-17 inhibitors, which have recently been shown effective in PsA and AS, would not be a good choice for IBD related arthritis as they can have a detrimental effect on bowel inflammation.

Arthur Kavanaugh, MD1, Abha Goyal Singh, MD2 1Professor of Medicine Director, Center for Innovative Therapy Division of Rheumatology, Allergy and Immunology, 2Assistant Professor of Medicine, Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, CA

INTRODUCTION

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, are chronic autoimmune diseases of the gastrointestinal tract that affect over 1.6 million Americans, with a rising global incidence and prevalence.1 These diseases cause significant morbidity, with frequent hospitalizations, surgery, and use of corticosteroids and immunosuppressive medications. Annual direct and indirect healthcare costs of IBD are estimated between $14.6-31.6 billion, with over 50% attributable to hospitalization-related costs. Beyond gastrointestinal symptoms and complications, IBD is a systemic disease that is frequently accompanied by extraintestinal manifestations (EIM) involving virtually every organ in the body. Extraarticular manifestations can add to the detrimental impact that IBD has on affected patients in terms of pain, quality of life and functional status.

Among extraintestinal manifestations of IBD, those affecting the musculoskeletal system are among the most common, and have been reported in several series to affecting from 6 to 46% patients.2,3 Indeed, from a rheumatology standpoint, IBD-associated arthritis, or ‘enterpathic arthritis’, has been considered to be within the family of conditions grouped under the title ‘spondyloarthropathies’ (SpA). Also included within this category are psoriatic arthritis (PsA), ankylosing spondylitis (AS) and reactive arthritis. There is growing understanding of the immunopathophysiology of these conditions, highlighting common alterations in the immune and inflammatory responses common to diseases with potentially diverse clinical manifestations. In addition, there are increasing therapeutic options for patients with SpA, with some agents more or less effective for specific manifestations. A number of agents used to treat SpA have also shown efficacy in IBD, highlighting some common aspects of immune dysregulation across these conditions.

Epidemiology

Joint involvement is the most common extraintestinal manifestation of IBD, affecting up to 46% of patients.2,3 In addition to non-inflammatory arthralgias without actual swollen joints, seen in 8-30% of patients, inflammatory arthritis of the spine (also called axial disease) or the peripheral joints have been clearly demonstrated. Early reports classified peripheral arthropathies into type I pauciarticular (four or fewer peripheral joints) or type II polyarticular (five or more peripheral joints involved). More recent work has shown that patients may present early with fewer joints involved and over time evolve into a polyarticular phenotype. In addition to peripheral arthritis, patients may have axial arthritis. Such patients typically present with inflammatory back pain, generally defined as pain that occurs in younger adults (e.g. less than 40 years of age), is worse in the morning, improves with use and responds clinically to non-steroidal anti-inflammatory drug (NSAID) therapy. Another area of inflammation common to SpA conditions is enthesitis. Entheses are areas where tendons, ligaments and joint capsules insert into bone. Inflammation at the entheses is not only common, but may be an early and perhaps etiopathogenically relevant aspect of SpA, including IBD related arthritis. While musculoskeletal involvement most often develops following the diagnosis of IBD, in a small subset of patients (<5%) articular symptoms may precede IBD. Risk factors for articular manifestations among IBD patients have been suggested to include a family history of IBD, appendectomy, cigarette smoking and the presence of other extraintestinal manifestations such as erythema nodosum or pyoderma gangrenosum.4 Patients with extensive colitis (rather than proctitis) patients with colonic Crohn’s disease have been suggested to be more likely to develop articular EIMs.

As more effective therapies have become available for the treatment of peripheral arthritis, axial arthritis and enthesitis, early recognition has become even more important. Some signs and symptoms that could prompt consideration of inflammatory musculoskeletal involvement in an IBD patient include chronic (e.g more than three months) back pain, peripheral joint pain and swelling, enthesial tenderness and dactylitis (swelling of an entire digit due to abundant arthritis and tenosynovitis).5

Pathophysiology

Rheumatologic manifestations in patients with IBD have been hypothesized to be due to articular and peri- articular homing of activated intestinal lymphocytes; these data suggest the presence of a ‘gut-joint axis’.6 In patients with IBD, lymphocytes of various subtypes may access articular sites using multiple adhesion molecules and their counter receptors. In addition to aberrant lymphocyte homing, dysbiosis, or an alteration in the diversity of gut microbiota, may be another shared pathophysiological mechanism between IBD and IBD- associated arthritis.

Clinical Presentation and Diagnosis
Peripheral Arthropathies

Peripheral arthritis in IBD typically presents as inflammatory arthritis, with joint pain and swelling. Traditionally, IBD-associated arthritis had been considered to be generally non-erosive and non- destructive; however, there is the possibility that these considerations were tautologic, and therefore this may not be an accurate distinction.3,4,5

Early reports classified peripheral arthropathies into so-called type I pauciarticular (four or fewer peripheral joints) or type II polyarticular (five or more peripheral joints involved) (Table 1). More recent work has shown that patients may present early with fewer joints involved and over time evolve into a polyarticular phenpotype. The most important distinction is the number of joints involved. Patients with oligoarticular disease are more likely to have a more favorable prognosis over time. In contrast, those with polyarticular disease, either at onset or later in the disease course, are more likely to suffer impaired functional status and quality of life. IBD associated arthritis, as a SpA related condition, is distinct from rheumatoid arthritis that could also occur in IBD patients. Supporting this are the lack of correlation between IBD arthritis and antibodies to citric citrullinated peptides (anti-CCP).6

Axial Arthritis

Axial involvement is a common feature of IBD- associated arthritis. The prototypical symptom is inflammatory back pain; other features of ankylosing spondylitis have been clearly demonstrated in patients with arthritis associated with IBD.3,4,5 These are more frequently observed in patients with Crohn’s disease (5-22%), as compared to ulcerative colitis (2- 6%).

Inflammatory back pain is characterized by insidious onset of back pain, lasting more than three months, associated with morning stiffness and improvement with exercise. Ankylosing spondylitis has been traditionally diagnosed based on a combination of inflammatory back pain symptoms, limitation of spinal flexion (Schober’s test) and reduced chest expansion and X-ray imaging showing bilateral sacroiliitis grade ≥2 or unilateral sacroiliitis grade 3-4. There appears to be a genetic association between ankylosing spondylitis and IBD. Approximately 5-10% patients with ankylosing spondylitis develop IBD, and up to 70% patients may have microscopic evidence of gut inflammation; likewise, about 5-10% patients with IBD may develop ankylosing spondylitis.6 The presence of an elevated C-reactive protein and serum and/or fecal calprotectin in patients with ankylosing spondylitis has been shown to have modest accuracy as a screening strategy to identify potential ankylosing spondylitis patients with gut inflammation. Most patients with ankylosing spondylitis are HLA-B27 positive. Patients with IBD and axial arthritis have a rate of HLA-B27 positivity far above the general population (∼50%) but lower than those patients with AS. Regarding the diagnosis of axial inflammatory arthritis, magnetic resonance imaging (MRI) is often considered the gold standard. Changes on plain X-ray are more specific for the diagnosis of AS, but are less sensitive.

Other Musculoskeletal Extraintestinal Manifestations of IBD

Besides peripheral and axial arthropathies, enthesitis, tenosynovitis and dactylitis are commonly observed, particularly if highly sensitive imaging techniques such as ultrasound are utilized.5

Rheumatic Complications in IBD

While osteoporosis is not perhaps strictly an extraintestinal manifestaition of IBD, it is indeed a frequently observed complication, occurring in about 14-42% patients.3,4 It is multifactorial, and related to a number of factors including intestinal malabsorption due to active disease or surgical resections, recurrent exposure to corticosteroids, and the local and systemic effects of chronic systemic inflammation. National guidelines suggest screening IBD patients with conventional risk factors for osteoporosis with dual energy X-ray absorptiometry.

Treatment

Arthritis can be functionally limiting in patients with IBD, and hence warrants attention and treatment in symptomatic patients.

Much of the data relevant to the treatment of peripheral arthritis related to IBD comes from the literature on the treatment of psoriatic arthritis (PsA) with peripheral arthritis. Treatment options include disease modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX), sulfasalazine, leflunomide and apremilast. Among biologic agents, tumor necrosis factor inhibitors (TNFi) have the longest and largest clinical data supporting their substantial efficacy. The most relevant data concerning the treatment of spinal, also called axial, arthropathies comes from studies of patients with ankylosing spondylitis. While NSAIDs and specific cyclooxygenase 2 (COX2) inhibitors are effective in both peripheral and axial arthritis, their use in IBD must take into account their potential effects on the bowel. Short courses (less than two weeks) of NSAIDs, particularly, COX-2 inhibitors may be used in patients with IBD.7 However, caution should be exercised since NSAIDs may exacerbate underlying IBD. In a large prospective cohort study of 791 patients with IBD in clinical remission at baseline, frequent use of NSAIDs ≥5 times per month was associated with 1.7 times higher risk of flare of Crohn’s disease, but not of ulcerative colitis; less frequent use was not associated with risk of IBD exacerbation.8 In a meta-analysis of 7 studies with 344 patients with IBD, about 14.4% patients treated with NSAIDs experienced exacerbation of gastrointestinal symptoms.9

While DMARDs are ineffective for axial arthritis, TNFi are highly effective. IL-17 inhibitors, which have recently been shown effective in PsA and AS, would not be a good choice for IBD related arthritis as they can have a detrimental effect on bowel inflammation.

Given the considerable overlap in IBD and rheumatic diseases, the concept a multi-disciplinary approach in a combined gastroenterology-rheumatology clinical has been explored. In a prospective study of 269 IBD patients with joint pain, Canigliaro and colleagues observed that a diagnosis of enteropathic arthritis was made in 50.5% of IBD patients with joint pain. These patients had peripheral arthropathies in 53%, axial arthropathies in 20.6% and both peripheral and axial arhropathies in 26.4% patients. These patients had higher prevalence of other EIMs and received more anti-TNF treatment compared with IBD patients without enteropathic arthritis.10 The mean diagnostic delay of 5.2 years was revealed in these patients; however, with the creation of a combined clinic there was a considerable decline in diagnostic delay.

In summary, rheumatologic extraintestinal manifestations and complications are common in patients with inflammatory bowel disease, presenting as peripheral arthritis and/or axial arthritis. These may or may not be related to IBD disease activity, but can cause considerable impairment of quality of life. A high index of suspicion and early treatment may decrease healthcare burden.

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Frontiers In Endoscopy, Series #36

Current Practice Patterns for Esophageal Stenting in Malignancy – A Web-Based Survey of Endoscopists Who Place Self Expanding Metal Stents

May 2017 • Volume XLI, Issue 5
David L. Diehl,Jessica McKee,Amir N. Rezk,Douglas G. Adler,Kimberly Fairley,Harshit S. Khara

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Dysphagia is the most common presenting symptom in patients with advanced esophageal cancer (EC). Difficulty managing oral secretions and eating solid food has a significant negative impact on their quality of life. In the current clinical environment, there is an understanding of the risks and benefits of self-expanding metal stents (SEMS) for malignant dysphagia, with most patients having excellent clinical outcomes and serious adverse events being relatively uncommon. To analyze trends in esophageal SEMS, we conducted a web-based survey to better understand the practice patterns of physicians who place SEMS and to poll their opinions about unmet needs in this clinical space.

David L. Diehl, MD reports consulting role with Boston Scientific and Olympus America. Douglas G. Adler, MD reports consulting role with Boston Scientific. David L. Diehl, MD1 Jessica McKee, DO1 Amir N. Rezk, MD1 Douglas G. Adler, MD2 Kimberly Fairley, DO1 Harshit S. Khara, MD1 1Geisinger Medical Center, Danville, PA 2Huntsman Cancer Center, University of Utah, Salt Lake City, UT

Background
The practice of placing self-expanding metal stents (SEMS) for esophageal cancer remains non-standardized regarding patient selection, timing, type, duration, and adverse event management.

Aims
To understand current practice patterns of SEMS placement and unmet needs by experts.

Methods
An 18-item on-line survey evaluated practices and preferences for SEMS by experienced advanced endoscopists (gastroenterologists and surgeons). Questions investigated stent types and sizes, methods and timing of deployment, perceived problems and unmet needs of currently available SEMS, and other issues.
Results 46 (22%) physicians responded. 51% made the decision to proceed with SEMS; 49% did after oncology request. 86% use SEMS prior to neoadjuvant treatment; 29% routinely remove SEMS at the end of radiation. 89% still observe feeding tube use instead of SEMS. Fluoroscopic placement was used by 74%. Endoscopic tumor palliation is uncommonly done (17%). Larger diameters (22-23mm) are used most commonly (59%); 52% have used SEMS < 18mm. Problems with SEMS included migration (62%), reflux (49%) and pain (56%) which infrequently requires SEMS removal. Tumor overgrowth/ingrowth was seen by 29%.

All respondents agreed that there was need for improvement of available SEMS. 62% expressed an interest in biodegradable SEMS and 60% felt that having a stent with anti-reflux functionality would be of benefit. Other unmet needs for SEMS included less radial force (51%) and better conformation to the GE junction angle (36%).

Conclusions
The use of esophageal SEMS remains non-standardized in clinical practice. Common themes regarding current usage were found. There are unmet needs regarding current stent technology.

INTRODUCTION

Dysphagia is the most common presenting symptom in patients with advanced esophageal cancer (EC). Difficulty managing oral secretions and eating solid food has a significant negative impact on their quality of life. In the current clinical environment, there is an understanding of the risks and benefits of self-expanding metal stents (SEMS) for malignant dysphagia, with most patients having excellent clinical outcomes and serious adverse events being relatively uncommon.1 In addition, the clinical characteristics of patients who may need SEMS has changed with the widespread use of neoadjuvant treatment regimens for patients with locally advanced EC. The practice of placing esophageal SEMS remains non-standardized with regards to issues such as patient selection, timing of SEMS placement, type of SEMS placement in a given clinical situation, duration of SEMS placement, and management of SEMS-induced adverse events. To analyze trends in esophageal SEMS, we conducted a web-based survey to better understand the practice patterns of physicians who place SEMS and to poll their opinions about unmet needs in this clinical space.

Methods

An 18-item survey instrument was designed to evaluate current practices and preferences for SEMS. Questions were designed to not focus on any particular brand of stent, but general preferences in stent selection and clinical scenarios when stents are used. In addition, the survey questions were designed to try to elicit endoscopist’s perceptions of unmet needs given the current stent technology. The survey was uploaded to an on-line survey service (Survey Monkey, Palo Alto, CA), and went live for a 12-week period from December 2014-February 2015. The survey asked respondents questions regarding technical issues involving stent types and sizes, methods of deployment, and clinical issues regarding which patients received stents and when this occurred in the continuum of their care. Respondents were also questioned on their use of other palliative modalities in the treatment of dysphagia associated with EC. In addition, respondents were asked to elaborate on what they perceive as problems and unmet needs of currently available SEMS (See appendix for the entire survey instrument). Respondents were not paid for their participation.

This survey was sent to endoscopists and surgeons throughout the United States. Physicians who were involved in advanced endoscopy training were identified from the ASGE listing of advanced endoscopy programs.2 Surgeons who place esophageal stents were identified from esophageal stent sales data obtained from stent manufacturers. These physicians were included and contacted by email. An introductory message was sent to each physician along with the link to the survey. Completion of the survey signified implied consent for participation in the study. Our study was completely accomplished by survey and there was no other interaction with the subjects; i.e. there was no patient contact and no patient risk. IRB approval was obtained prior to commencing this study.

Results

The on-line survey was sent to 208 physicians, and 46 (22%) responded (Table 1). There were 39 gastroenterologists and 7 surgeons. 91% had an academic practice, while 9% identified themselves as being in private practice (with 7% in private practice but having an association with a gastroenterology fellowship). Regarding the initial decision to proceed SEMS placement, 49% physicians placed SEMS after multidisciplinary EC management team discussion; 51% made the decision to proceed with SEMS autonomously. 86% of practitioners have placed SEMS prior to neoadjuvant treatment, and 37% will schedule a planned removal at the end of radiation therapy. 89% of respondents observed placement of gastric or jejunal feeding tubes for nutrition instead of SEMS. The use of endoscopic tumor ablation instead of stenting was reported in 38% of respondents.

The majority of providers (74%) utilized fluoroscopy for SEMS placement while 26% used only endoscopic guidance for SEMS placement. Larger stent diameters (22 or 23mm) are used most commonly (59%) while 39% prefer the 18mm stent and only 2% of providers use stents less than 18mm (Figure 2). The 16 mm or smaller stents were used for indications of a very tight obstruction, pain from previous stent, pediatric application, or placement in the cervical esophagus (Figure 3).

Problems reported with SEMS included migration (62%), reflux related to use at the GE junction (49%) and problematic pain after placement (56%) (Figure 4). 91% of respondents have had the experience of having to remove a stent within a month of placement due to intractable pain; however, in general stent removal was required infrequently (Table 1). Stent migration was encountered by 62% of respondents, and tumor overgrowth / ingrowth by 29% (Figure 4).

All of the respondents agreed that there was need for improvement on the available SEMS. The majority of endoscopists expressed an interest in biodegradable SEMS (62%) and felt that having a stent with anti-reflux functionality would be of benefit (60%). Other unmet needs for SEMS in the United States included the need for stents with less radial force (51%) and stents that conform better to the angle of the GE junction (36%) (Figure 5).

DISCUSSION

Self-expanding esophageal metal stents are in widespread use and allow patients to achieve rapid palliation of dysphagia from a variety of benign and malignant causes.3 Despite this, the use of these devices remains nonstandardized in clinical practice. We undertook a survey to evaluate usage of, and perceptions about these devices in current gastroenterology practice. We present here the results of this survey to provide insight into the prevailing practice patterns of gastroenterologists who commonly place esophageal SEMS. A variety of E-SEMS have been developed for the palliation of malignant dysphagia and there may be a variety of factors influencing how endoscopists select a particular stent. Tumor length and position, the presence or absence of a fistula, potential airway compromise in the setting of proximal stenosis and personal preference may all influence the endoscopist’s choice. The use of smaller esophageal stent diameters to try to decrease post-treatment pain has been advocated,4 however most of our respondents continue to use the largest stent diameters (59% use 22 or 23mm stents, 39% use 18mm), and only 2% used stents smaller than 18mm. A prospective randomized study compared 18mm versus 23mm SEMS.5 Adverse effects were seen in both groups, but the type of incidents were somewhat different, with more migration, stent occlusion, and need for repeat endoscopy in the small diameter groups and more bleeding and esophagorespiratory fistulas in the large diameter group. The use of smaller diameter stents (16 mm or less) has been utilized in patients with very tight strictures in a limited number of studies. Kucera et al.6 compared small caliber SEMS (10mm-16mm) to large caliber SEMS (>18mm). Stent- related pain was decreased although migration during therapy was increased 5.5 fold. There was comparable dysphagia reduction when the two different stent types were compared.

Chest pain in patients after SEMS placement was described by more than half of respondents (56%). The exact cause of pain after SEMS deployment is not clear and is likely multifactorial, including radial force, axial force (resulting in pressure against the esophagus from the ends of the stent), GERD, primary tumor pain, and other factors. The optimal radial force for SEMS has not been determined, and it is likely variable in different patients. Half of respondents felt that having stents with less radial force may be beneficial in decreasing pain after placement.

It has been reported that up to 79% of esophageal cancer patients are malnourished even before treatment begins.7 One study of 138 patients with GEJ EC found that “individualized goal-directed dietary counseling” could almost completely allow avoidance of SEMS as well as external feeding tubes. Dysphagia resolved after the first cycle of chemotherapy, and an SEMS was required in only one patient.8 Among respondents to the survey, 89% observe use of surgical jejunostomy or gastrostomy, which may reflect referring physician’s lack of faith in the inability of an esophageal stent to allow the patient to maintain their nutritional status orally. The belief that SEMS would make feeding tubes unnecessary has not been fully realized and the presence of an external tube is a constant reminder to the patient of their diagnosis.99

The emergence of neoadjuvant chemoradiation therapy as a preferred approach to treatment of esophageal cancer has introduced another large change in the landscape of the use of SEMS. Data is mixed on whether the use of SEMS in the neoadjuvant setting leads to negative outcomes,1,10,11 or does not.9,12-15 Eighty six percent of the respondents do use SEMS in the neo-adjuvant setting, and many (33%) indicated that removal is scheduled routinely at or near the end of the radiation treatment. The decision as to which patients should receive SEMS prior to neoadjuvant treatment may be made by the endoscopist (51% of respondents) or by a multidisciplinary oncology treatment panel (49%). The interventional endoscopist would be well-advised to discuss stent placement with a multidisciplinary oncology group prior to placement depending on institutional practices.

60% of respondents felt that having a stent with anti-reflux functionality would be of benefit. A stent with anti-reflux technology was previously available in the United States and decreased reflux symptoms after placement,16 but technical problems led to the device being withdrawn from the market. A newer stent with an anti-reflux valve (EndoMAXX EVT, Merit Medical, South Jordan, UT) has been used clinically in Europe with encouraging results. A prospective randomized study is currently under way in the United States (EVOLVE Study, # NCT02159898) to assess the usefulness of the EndoMAXX EVT stent.17

About a third of respondents (36%) felt that there may be some benefit to having stents that conform better to the geometry of the GE junction. The tumor histology of malignant esophageal obstruction has changed from predominantly squamous cell carcinoma, most commonly located in the mid esophagus, to adenocarcinoma with a distal esophageal or gastroesophageal junction (GEJ) location. Straight stents are not always positioned optimally at the GEJ location, and in rare cases may obstruct if they are impacted against gastric or esophageal lumen (Figure 6).

A majority of respondents (62%) felt that one of the unmet needs in the field was having biodegradable SEMS available for use. This technology could theoretically improve issues related to stent migration, post-deployment pain, and conformation to the GEJ, if the optimal specifications could be engineered into the stent. A biodegradable stent made from polydioxanone (ELLA-CS, Hradec Kralove, Czech Republic) has been available in Europe and the UK since at least 2008. A number of studies have been done for both malignant and non-malignant esophageal strictures.18 This device is not FDA approved for use in the United States. Biodegradable stents may play a role in the management of refractory benign strictures,19,20 and their use has been included in the treatment algorithm of refractory strictures.21 Newer technology may utilize magnesium compounds as the biodegradable scaffolding.22

Thirty eight percent of respondents use ablative techniques as an alternative to SEMS in some cases of malignant dysphagia. In the past, APC, Nd:YAG laser, photodynamic therapy (PDT) and a specialized bipolar cautery ablation probe (BICAP Tumor Probe, Circon USA) all saw some use for treating esophageal obstruction.23-26 All techniques required specialized equipment and expertise, and usage essentially ceased shortly after SEMS were introduced. Recently, a renewed interest in cryoablation has led to a number of advanced endoscopists using this treatment as a palliative approach for obstructing esophageal cancer.26 It may be a good option in the neoadjuvant setting, if studies demonstrate that one or two endoscopic ablation sessions are all that is required for palliation of dysphagia until the chemoradiation effect opens the esophageal lumen.

Endoscopists who place SEMS may not have further interaction with that patient, as their care is transitioned to medical, radiation and surgical oncologists. Stent- related problems may occur without the knowledge of the endoscopist. As a result, these other care-givers may develop a negative perception of SEMS, and try to avoid their use, particularly in the neo-adjuvant setting. The experience of even a single patient having a stent- related problem is often enough to make an oncologist or surgeon avoid referring patients for SEMS in the future. This may lead to underuse of SEMS in patients that could in fact benefit from them.

Esophageal SEMS have in the past and continue to play an important role in the management of malignant dysphagia. There is a large amount of data showing that these devices are safe in both the palliative and neoadjuvant treatment settings. Technical and clinical success rates with esophageal SEMS are high.

Physicians who place SEMS should have a realistic view of their benefits and the potential short- comings of these devices. Close collaboration between interventional endoscopists and oncology care providers is important so that treatment plans for patients with malignant esophageal obstruction can be optimized. In this way, the largest number of patients who might benefit from this technology can receive it.

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Nutrition Issues In Gastroenterology, Series #163

Pancreatogenic Type 3c Diabetes – Underestimated, Underappreciated and Poorly Managed

May 2017 • Volume XLI, Issue 5
Sinead N. Duggan,Kevin C. Conlon

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Type 3c diabetes, also known as pancreatogenic diabetes, refers to diabetes resulting from pancreatic disease, including pancreatitis, cystic fibrosis and pancreatic cancer. It is difficult to diagnose, and for many, management is challenging due to erratic swings from hypoglycemia to hyperglycemia caused by metabolic abnormalities due to pancreatic tissue damage. This review aims to describe the disease along with its characteristics, diagnosis, complications, and management.

Sinead N. Duggan RD PhD, Research Fellow, 1.29 Department of Surgery. Professor Kevin C. Conlon MD, Professor of Surgery, 1.36 Department of Surgery, Trinity Centre for Health Sciences,Tallaght Hospital, Trinity College Dublin, Tallaght, Ireland

CLINICAL CASE 1

A 42 year old male with an eight-year history of alcohol-induced chronic pancreatitis was admitted from the ER. His current weight was 61Kg as opposed to his usual weight of 67Kg; his appearance was cachectic. He reported abdominal pain, intermittent diarrhea/steatorrhea along with periods of constipation, cramping, flatulence and poor appetite. He was not compliant with prescribed pancreatic enzyme replacement therapy (PERT), was still abusing alcohol, and was a heavy smoker for many years. He took opiates for relief of chronic, constant abdominal pain. His dietary intake was minimal over the past week and poor for several years. He was admitted and re-educated regarding adequate dietary intake, prescribed oral nutritional supplements, and counselled on adequate and appropriate usage of PERT. Blood work revealed low levels of serum vitamins (25 OHD, vitamin E and vitamin A), normal fasting glucose and HbA1c. He was discharged after 3 days once he was established on adequate oral diet, micronutrient supplementation, PERT, and his pain medication had been adjusted. He was readmitted three weeks later with dehydration, fatigue, excess thirst and blurred vision. Fasting glucose was measured and was elevated at 250 mg/dl (13.9 mmol/L), therefore new diabetes mellitus (DM) was diagnosed. A referral was made to the endocrinology service for further evaluation.

CLINICAL CASE 2

A 37 year old female with a five-year history of type 2 diabetes mellitus (T2DM) presented to the gastroenterology outpatient clinic complaining of a 6 month history of diarrhea (3-4 times per day), flatulence and bloating. She had taken anti-diarrheal medication with limited effect. She reported that the diarrhea tended to occur post-prandially, and was worse with larger, ‘richer’ meals. She reported that she could see visible oil in the toilet pan after defecating, requiring several flushes. She also had a history of three episodes of hypertriglyceridemia-induced acute pancreatitis. On one occasion the acute pancreatitis had been deemed ‘severe’ and she was hospitalized for several weeks, including one week in the critical care unit requiring enteral feeding. She was 88Kg (BMI 30.4 Kg/M2). Given her history of acute pancreatitis, and the oily nature of her stools, pancreatic exocrine insufficiency (PEI) was suspected and a fecal elastase-1 test ordered. Results showed faecal elastase-1 of 95µg /g (indicating severe PEI). She was referred to a pancreatologist for further workup and pancreatic imaging.

INTRODUCTION

According to the American Diabetes Association (ADA), there are four DM subgroups. Most are familiar with type 1 diabetes (T1DM), an immune- mediated condition associated with beta-cell destruction leading to absolute insulin deficiency. T2DM is well recognized as a spectrum involving varying degrees of peripheral insulin resistance and beta cell dysfunction. Type 4 DM refers to gestational or pregnancy-related diabetes.1 This review will focus on Type 3 DM, categorized by the ADA as ‘other specific types of diabetes’. In particular we will focus on type 3c diabetes (T3cDM), which refers to DM arising from diseases of the exocrine pancreas. T3cDM is also referred to as pancreatogenic or apancreatic DM. A study from Europe on the reclassification of nearly 2,000 patients with DM reported that 8% of patients should have been diagnosed with T3cDM, rather than T1DM or more usually, T2DM.2 Three-quarters of the patients reclassified as having T3cDM had chronic pancreatitis, while the rest had haemochromotosis, cystic fibrosis, or were pancreatic cancer patients. Therefore, this study showed that T3cDM was reasonably common. Several clinical and biochemical indices distinguish T3cDM from T1DM and T2DM (see Table 1). Due to its association with pancreatic disease, patients are more likely to be undernourished or have nutrient deficiency.3 Pancreatic exocrine insufficiency (PEI) will also be a feature resulting in fat malabsorption. The management of patients with T3cDM is challenging due to a number of metabolic features (especially low glycogen stores due to malnutrition making counter- regulation difficult, normal glycated hemoglobin due to long standing poor nutrient absorption, then sudden nutrient utilization once PERT initiated, exaggerated response to smaller doses of insulin to name a few) resulting in severe swings in glucose levels from hypoglycemia to hyperglycemia, which in its most severe form is termed, ‘brittle diabetes’.

PREVALENCE OF T3cDM

While the study from Germany by Ewald and colleagues found that 8% of all diabetes patients had T3cDM, most of which had chronic pancreatitis, the occurrence of T3cDM in this disease actually ranges widely from 5% to more than 80%. It is higher in patients who have undergone surgical resection, especially of the distal pancreas.4 Smoking,5-7 longer duration of disease,4,8 and the presence of pancreatic calcifications4,9,10 increases the likelihood of developing DM in chronic pancreatitis. In general, it is thought that T3cDM is vastly underestimated. With the increased rates of pancreatic surgery and pancreatectomy, the increasingly higher survival of cystic fibrosis patients, and the increasing prevalence of chronic pancreatitis world-wide, T3cDM is of growing importance.11

DIAGNOSIS AND DIFFERENTIATION OF T3cDM

Initial diagnosis of T3cDM (as for types 1 and 2), includes measurement of fasting glucose and glycated hemoglobin (HbA1c or A1c), repeated annually for those with pancreatitis. Equivocal results should arguably be investigated further by means of an oral glucose tolerance test.12 The ADA guidelines state that fasting plasma glucose of >126 mg/dl (>7mmol/L) or HbA1c of >48 mmol/mol (6.5%) are diagnostic of DM, while a fasting glucose of 100-125 mg/dl (5.5-6.9mml/L) or HbA1c of 39-46 mmol/mol (5.7- 6.4%) are indicative of prediabetes.1,13 However, differentiating T3cDM from T1DM and T2DM is not always straightforward.14 Destruction of the islet cells by pancreatic inflammation differs from that in T1DM as there is also a loss of glucagon and pancreatic polypeptide (PP) from the islet alpha cells and PP cells (as well as the loss of insulin from the islet beta-cells). Additionally, nutrient maldigestion and malabsorption lead to impaired incretin secretion and therefore diminished release from the remaining beta cells. Although circulating insulin levels are known to be low in T3cDM, along with a compensatory increase in peripheral insulin sensitivity, there is a decrease in hepatic insulin sensitivity (and unsuppressed hepatic glucose production), which drives hyperglycemia (see Table 1). The impairment of hepatic insulin sensitivity and persistent hepatic glucose production is associated with the reduction in pancreatic PP secretion.11 Therefore, the DM associated with pancreatic disease is erratic in nature, characterized by significant swings in blood glucose from hypoglycemia to hyperglycemia in a manner which is difficult to control.

Ewald and Hardt14 devised diagnostic guidelines for T3cDM, providing useful major and minor criteria which suggest a diagnosis of T3cDM. Major criteria which must be present include:

  • 1. Pancreatic exocrine insufficiency
  • 2. Pathological pancreatic imaging
  • 3. Absence of T1DM-associated auto-antibodies.

The minor criteria were absent PP secretion, impaired incretin secretion, absence of excessive insulin resistance, impaired beta-cell function, and low serum levels of fat-soluble vitamins.

Assessment and monitoring of patients with pancreatic disease should include body mass index, diabetes-associated antibodies (to out rule T1DM), and glucose to c-peptide ratio which estimates beta- cell area.12 Insulin resistance is measureable by the homeostasis model assessment, which estimates steady state beta-cell function and insulin sensitivity as percentages of a normal reference range. This is calculated based on fasting plasma glucose and insulin values. Unlike T2DM patients, those with T3cDM will not normally have excess insulin resistance. The absence of (or reduced) PP secretion following ingestion of glucose or a mixed meal may also be indicative of T3cDM.14 However, these guides require the measurement of incretin, PP and c-peptide levels, among others, which in everyday practice is unlikely to occur. Table 1 compares the clinical and laboratory characteristics of T3cDM with that of T1DM and T2DM, which is an expansion of earlier versions by Slezak and Andersen15 and Cui and Andersen.11

While T3cDM has features which overlap with both T1DM and T2DM, it is clinically and metabolically distinct from both, having unique characteristics and specific management priorities requiring tailored therapy. The additional complication of nutrient malabsorption, and frequently poor oral diet (to avoid symptoms), including chronic pain; smoking and/or alcoholism), renders the T3cDM patient at high risk of undernutrition and critical hypoglycemia. In clinical case 1, the patient did not present with gross steatorrhea as one might expect in advanced chronic pancreatitis (but remember one has to eat fat to malabsorb it – often intake can be so poor, this is another reason why it is missed), therefore it might be perceived that the small amounts of PERT taken was adequate to counteract PEI. However, once normal diet resumed and PERT dosage/administration were optimized (allowing optimal absorption of nutrients including carbohydrate), there was an ‘unmasking’ of his DM. In patients who already have a diagnosis of DM, there may be a profound worsening of hyperglycemia. Where patients take opiates due to chronic pain, constipation may be a surprising feature of chronic pancreatitis, leading the clinician to believe that PERT is adequate or unnecessary, contributing to undernutrition and nutrient deficiency. In clinical case 2, our patient with DM had undiagnosed PEI demonstrating that altered pancreatic function should be considered in diabetic patients with intractable gastro-intestinal symptoms, particularly those with a history of pancreatic disease.

COMPLICATIONS OF T3cDM

Retinopathy, renal dysfunction, neuropathy and microangiopathic complications appear to occur as frequently in T3cDM as in T1DM and T2DM.16-19 It is thought that macrovascular complications occur less frequently due to chronic malabsorption and commonly- occurring undernutrition, however research and long- term studies are lacking and the risks are incompletely understood.

PHARMACOLOGICAL TREATMENT OF T3cDM

There are few, if any, studies on the pharmacological treatment of T3cDM. In fact, patients with T3cDM were specifically excluded from many large-scale DM studies due to their unique, eccentric clinical and metabolic characteristics. In chronic pancreatitis, for those with severe undernutrition, insulin is usually required to control blood glucose levels. Notably, Cui et al. have cautioned against using insulin in chronic pancreatitis (calling it a ‘pre-malignant condition’).11 It should be noted that the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial,20 which included patients with impaired fasting glucose, impaired glucose tolerance and T2DM, showed that there was no increase in incident cancers for those on insulin glargine versus standard care. The risk of developing pancreatic cancer for those with chronic pancreatitis is higher than the general population, and for those with T2DM, the risk of developing pancreatic cancer is twice that of the general population. However, those with T2DM are at a higher risk for many cancer types, so the risk is not confined to pancreatic cancer alone.21 In fact, many will require insulin to control rampant hyperglycemia, and its anabolic effects are welcome in those with undernutrition. For those with more mild hyperglycemia and concomitant insulin resistance, metformin could be used if not contraindicated, although it may cause gastrointestinal side-effects such as nausea and diarrhea, unwelcome additions in pancreatic disease. Even where insulin therapy is required, metformin and other oral hypoglycemic agents could be used to reduce the requirement for large amounts of insulin.22

NUTRITIONAL MANAGEMENT OF T3cDM

The PancreasFest Working Group23 were the first to provide a diagnostic and management framework for T3cDM in chronic pancreatitis. They recommended that patients with T3cDM should be treated with specifically-tailored medical nutrition, and that the primary goals are to prevent or treat malnutrition, control symptoms of the steatorrhea, and to minimize meal-induced hyperglycemia. Cui and Andersen stated that initial therapy should begin with correction of lifestyle factors which contribute to hyperglycemia and malignancy, including reinforcing weight loss for the obese, daily exercise, and limited carbohydrate, along with recommending abstinence of alcohol and smoking cessation at every medical visit.11

A recent review by Duggan et al. aimed to provide detailed dietary guidelines.12 In the first instance, dietary management should prioritize the prevention of hypoglycemic events and the provision of education regarding hypoglycemia symptoms and treatment (Table 2). A regular meal plan with specified, controlled amounts of starchy carbohydrate should be provided. Blood glucose should be monitored regularly (Table 3), with self-monitoring recommended especially for those on intensive insulin regimens. This is based on the ADA recommendations for T1DM and T2DM patients on intensive insulin regimens. The ADA did not provide a guide specifically for T3cDM, but given the risks of hypoglycemia and the difficulties in management, such a monitoring regimen could be implemented if tolerated by the patient. According to the ADA, such intensive monitoring regimes are probably not required for those on basal insulin plans, or for those taking oral hypoglycemic agents.

Those with ‘brittle’ DM in particular should maintain a record of blood glucose values, dietary intake, physical activity, and PERT usage to aid in dietary review and assessment.12 Continuous Glucose Monitoring (CGM) may have an important role in patients with brittle diabetes. The recently Food and Drug Administration (FDA)-approved DEXCOM (www.dexcom.com; San Diego, CA) G5 mobile CGM system is externally-worn glucose sensor which reports values every 5 minutes. This allows for the prediction of imminent hypo- or hyperglycemia, and reduces the requirement for multiple fingerstick blood glucose testing. The DEXCOM system uses algorithmic signal processing to convert raw electrochemical blood glucose values. Therefore the CGM system may allow for a reduction in HbA1c, without an increased risk of hypoglycemia.24

Alcohol, which will exacerbate hypoglycemia, should be avoided or minimized. The second priority is to reduce the frequency and extent of hyperglycemic events to minimize the risk of diabetes-associated complications. This includes minimizing simple sugar sources, especially in liquid form, and following a low- glycemic diet, where feasible. ‘Diabetic’ foods, which are expensive and may have a laxative effect in large quantities due to sorbitol (and other sugar alcohols) content, are generally not recommended. Adequate PERT, taken appropriately, is crucial to ensure nutrient absorption. Education around malabsorptive symptoms and dose titration should be provided.12 Management of T3cDM in pancreatic disease represents just one of the challenges in the nutritional management of this complex patient group. In both chronic pancreatitis and cystic fibrosis, regular anthropometric assessment, biochemical workup, and evaluation of bone health should accompany endocrine, exocrine and dietary evaluation.25,26 The ADA recommended that an individualized medical nutrition therapy program be established by a registered dietitian; specifically they recommended that an individualized eating plan be established. This recommendation, again, was for patients with T1DM and T2DM, but would also be vital in T3cDM.

CONCLUSION

In summary, T3cDM is a clinically important disease, which has to date been underestimated and underappreciated, and thus, tends to be poorly managed. As yet, there remain many research gaps regarding its diagnosis and management. Close, careful glycemic control, optimization of intestinal absorption and nutritional status, as well as to account for the complex array of factors contributing to this challenging condition.

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A Case Report

Duodenal Post-Transplant Lymphoproliferative Disorder (PTLD) with History of Heart Transplant

April 2017 • Volume XLI, Issue 4
Karen Tsai,Thomas Coppola,Raluca Vrabie

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Post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy in adult transplant recipients. We present a case of PTLD in the duodenum in a 48-year-old, Epstein-Barr virus positive female who underwent remote heart transplant due to postpartum cardiomyopathy. Her PTLD manifested as acute onset hypoalbuminemia and severe diarrhea. The diagnosis was made from duodenal biopsies, which looked mildly nodular. Remission of PTLD and symptom resolution were seen with reduction of tacrolimus and increase in valacyclovir doses. Although a rare entity, PTLD is a relevant clinical diagnosis in solid organ transplant patients who have unexplained diarrhea.

Karen Tsai, BA, MD Candidate1 Thomas Coppola, DO, Gastroenterology Fellow2 Raluca Vrabie, MD Director of the Center for Inflammatory Bowel Diseases2 1Stony Brook University School of Medicine, Stony Brook, NY, 2Winthrop University Hospital, Department of Gastroenterology, Mineola, NY,

INTRODUCTION

Post-transplant lymphoproliferative disorder (PTLD) is a serious and potentially fatal complication after solid organ transplant. It is the most common malignancy post solid organ transplant in adults and occurs in up to 10% of patients.1 With increasing number and improving survival of solid organ transplantations, clinicians should be aware of post-transplant complications. PTLD is an entity that is usually seen within the first few years post-transplant, mediated by the degree of immunosuppression and the EBV status of the patient. Clinical symptoms of PTLD can be highly variable, ranging from acute viral illness mimicking infective mononucleosis to organ-specific symptoms often making the diagnosis challenging.

Presentation

A 48-year-old female with a history of heart transplant 16 years ago from Coxsackie-induced postpartum cardiomyopathy presented to the hospital with complaints of fatigue and severe diarrhea for the past month. Her diarrhea was watery, non-bloody, occurring six times a day and unrelieved by intermittent loperamide use. She denied any sick contacts or recent travel. Her medical history consisted of renal insufficiency secondary to chronic tacrolimus toxicity, anal squamous cell cancer diagnosed two years ago (treated with surgery, Nigro chemotherapy and radiation), Epstein-Barr virus (EBV) infection, genital herpes and Kaposi sarcoma (excised). Her home medications included tacrolimus for transplant immunosuppression and valacyclovir.

On exam, she demonstrated whole body anasarca, abdominal ascites and 3+ pitting edema in her lower extremities bilaterally up to the knees and lower back. Her labs were significant for hypoalbuminemia (2.1g/dL; normal 3.5-4.8g/dL), and hypereosinophilia (absolute eosinophil 1.4K/uL; normal 0-0.5K/uL). Urinalysis was negative for hematuria and proteinuria. Tacrolimus level was 9.9ng/mL (normal 5-20ng/mL). An infectious gastroenteritis workup including ova and parasites, stool culture including Salmonella, Shigella, Campylobacter and Clostridium difficile was negative. Serum tissue transglutaminase and stool lactoferrin, pancreatic elastase and calprotectin were unremarkable. Liver enzymes were within normal limits.

The patient underwent upper endoscopy and colonoscopy with biopsies. The endoscopy was largely normal, with mildly nodular mucosa in the duodenal bulb (Fig. 1). The colonoscopy was grossly unremarkable. Pathology results from the duodenal bulb showed atypical lymphoid infiltrates consistent with PTLD and atypical cells that expressed CD20, CD79a and BCL-2 and were negative for CD10 (Fig. 2a, 3a). Small bowel mucosa showed eosinophilia and scattered cells tested positive for EBV (Fig. 2b). This atypical lymphoid infiltrate showed a kappa to lambda ratio of 8:1, which was consistent with her serum monoclonal gammopathy.

Her tacrolimus dose was decreased due to the development of PTLD. Her symptoms markedly improved, and she was discharged with repeat endoscopy and colonoscopy six months later. Repeat endoscopy with biopsies showed remission of PTLD (Fig. 3b). The patient continued to follow with her transplant physician and oncologist who recommended continuing the current dose of tacrolimus , evaluating the therapeutic level biweekly. Her valacyclovir was increased. After these medication adjustments, her albumin increased from 2.1g/dL to 3.7g/dL and she had complete resolution of diarrhea and anasarca.

Discussion

PTLD is a well-recognized complication that occurs after solid organ transplantation. It is primarily caused by a B-cell proliferation due to therapeutic immunosuppression after organ transplantation. Tacrolimus suppresses T cell immunosurveillance, which in certain circumstances can cause the EBV virus to proliferate in immunogenic tissues. Due to its high content of immunogenic tissue, the gut provides an ideal location for the proliferation of PTLD.

The prevalence of PTLD differs with different organ allografts, with the highest prevalence in multivisceral transplant recipients (13%-33% of cases), followed by bowel (7%-11%), heart-lung (9.4%), lung (1.8%-7.9%), heart (3.4%), liver (2.2%) and kidney (1%) recipients.2 PTLD can occur years after transplantation with no inciting factor. Risk factors of PTLD include previous EBV infection, recipient age (<10 and >60 years-old show greater risk), degree of immunosuppression and host genetic factors.3

Known manifestations of PTLD include gastrointestinal bleeding, weight loss, abdominal discomfort, nausea and diarrhea. Protein-losing enteropathy with hypoalbuminemia is the most sensitive sign of gastrointestinal PTLD.4 The duration of the post-transplant period is important because PTLD is most likely to develop in the first year following transplantation, with an incidence of 224 per 100,000 in the initial year, decreasing to 54 per 100,000 in the second year and 31 per 100,000 in the sixth year.5 Our patient’s presentation of PTLD happened 16 years after transplant which was quite unusual.

After tacrolimus and valacyclovir dose adjustments, our patient’s symptoms improved markedly. Although no standard formula exists, decreasing tacrolimus or cyclosporine by 50% is often recommended.6 Approximately 40% of patients respond to reduction in immunosuppression alone.7 It is important to note is that although her tacrolimus levels were not elevated at time of presentation, she still developed PTLD.

Antivirals such as valacyclovir can possibly reduce the incidence of PTLD by lowering EBV viral loads, especially since EBV infection is associated with PTLD in up to 8% of transplant recipients.8 Since the patient was taking valacyclovir for her genital herpes, this may help explain the late PTLD presentation. Current treatments, such as rituximab-based regimens, are starting to become more defined in B-cell lymphoproliferative disorders because they express CD20 and treatment with rituximab is considered to be relatively non-toxic compared with traditional chemotherapeutic agents.3 Currently, primary prevention of PTLD includes EBV vaccination and chemoprophylaxis via antivirals such as acyclovir or ganciclovir.8

PTLD is a serious and feared complication in the post-transplant patient. This case is unique because of the patient’s late presentation, dramatic response to adjustments in tacrolimus and valacyclovir and the fact that the patient developed PTLD in the setting of normal tacrolimus levels. Understanding PTLD and having a greater awareness is crucial due to its high mortality rate and late diagnosis. Further research on PTLD can focus on exploring universal screening techniques and defining preventative strategies and optimal therapy.

Learning Points

  • Consider PTLD in a patient with gastrointestinal symptoms with history of solid organ transplant
  • Diagnosis of PTLD is made by endoscopy and colonoscopy with biopsies so gastroenterologist consultation should not be delayed when there is suspicion of PTLD

Acknowledgements

We would like to thank Dr. Kristin Sticco from the Winthrop University Hospital Department of Pathology for providing the images.

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Dispatches From The Guild Conference, Series #3

Detecting and Managing Dysplasia in Inflammatory Bowel Disease: 5 Key Tips

April 2017 • Volume XLI, Issue 4
Fernando Velayos

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The field of IBD-related CRC prevention is evolving. Fortunately, important advances in disease management to control inflammation (primary prevention) as well as improved detection of precancerous lesions (secondary prevention) have transformed how we think about colorectal cancer and how we detect and manage dysplasia today even compared to 10 years ago. The following review discusses 5 key tips for detecting and managing dysplasia in patients with IBD today.

Fernando Velayos, MD, MPH, Professor of Medicine Co-Medical Director, Center for Crohn’s and Colitis University of California, San Francisco, CA

INTRODUCTION

Colorectal cancer (CRC) is a feared complication of inflammatory bowel disease (IBD). Long- standing inflammation of the colon, a feature of both ulcerative colitis (UC) and Crohn’s disease (CD) of the colon, can cause genetic and epigenetic changes that lead to neoplastic transformation called dysplasia. If dysplastic lesions are allowed to continue, they ultimately progress to cancer. It is well known that the risk of CRC is driven primarily by extent and duration of inflammation. Except for histological inflammation at colonoscopy, most other risk factors are not potentially modifiable such as family history of colon cancer, presence of pseudopolyps, primary sclerosing cholangitis and of course extent and duration of disease. Some of these non-modifiable risk factors therefore serve as ways of identifying at risk patients who should undergo screening and surveillance colonoscopy.

The field of IBD-related CRC prevention is evolving. Fortunately, important advances in disease management to control inflammation (primary prevention) as well as improved detection of precancerous lesions (secondary prevention) have transformed how we think about colorectal cancer and how we detect and manage dysplasia today even compared to 10 years ago.1 The following review discusses 5 key tips for detecting and managing dysplasia in patients with IBD today.

1. Look for Dysplasia in the Right Patient

Several published guidelines recommended colon cancer screening and surveillance in patients with inflammatory bowel disease. Although the data demonstrating cancer screening in IBD reduces CRC mortality are limited, they are balanced by data demonstrating reduction in CRC risk over time in surveillance programs.2 Three United States (US) based major gastrointestinal societies, American Gastroenterological Association (AGA),3 American College of Gastroenterology (ACG)4 and American Society of Gastrointestinal Endoscopy (ASGE)5 all endorse colonoscopy-based screening and surveillance in patients with IBD (Table 1).

The first key thing to note is that while patients with IBD may get frequent colonoscopy, this often occurs in the setting of active disease and work up of symptoms. In contrast, colonoscopy performed for the purpose of screening should occur when disease is quiescent and otherwise would not have been performed. Although obviously “opportunistic screening” can occur during a symptom-indicated colonoscopy, analogous to removing a polyp in the work-up of a non-IBD patient who has diarrhea or abdominal pain, the fact is that these should not be considered pure screening. Symptom-based colonoscopies performed in patients with IBD or those with active inflammation should not be considered strictly screening unless inflammation is minimal as inflammation can obscure the presence of dysplastic lesions.

Regardless of the guideline used, the three US- based guidelines all make a recommendation for a first screening colonoscopy and then a recommendation for subsequent colonoscopies assuming no dysplasia is found. Almost all recommend performing the first screening colonoscopy within 8-10 years after diagnosis or alternatively, symptom onset, in all patients regardless of extent. The exception is in patients diagnosed with primary sclerosing cholangitis where it should occur immediately after the diagnosis of PSC. The latter recommendation is based on epidemiologic data showing a significantly increased colon cancer incidence in patients with PSC and that PSC patients often have occult low-grade clinical inflammation, therefore making assessment of disease duration a challenge. Biopsies should be taken in the right and left colon as well as the rectum, as subsequent intervals should be based on the degree of histological inflammation.

Assuming the colonoscopy did not detect dysplasia, guidelines vary with regard to the next colonoscopy, but they all recommend more frequent colonoscopy than the general population. Patients with isolated proctitis, Crohn’s involving less than one third of the colon, or isolated small bowel Crohn’s, do not need subsequent intense surveillance as their risk of colon cancer approximates that of the general population. For all other patients, the intervals between colonoscopies for IBD patients vary between one and three years depending on the guideline with wide latitude regarding criteria for the subsequent interval. The British society of Gastroenterology Guidelines, not included in the table, risk stratifies subsequent colonoscopies based on degree of inflammation and other risk features so that patients with the lowest risk features may not need the next colonoscopy for five years. Such an extension to five years for surveillance has not formally entered into US-based guidelines, although not unreasonable for low risk patients with no evidence of pseudopolyps and no symptoms or evidence of inflammation on colonoscopy over many years.

2. Focus on Mucosal Abnormalities, Not Simply Random Biopsies During Colonoscopy

The classic technique for performing screening and surveillance involves taking 33 random biopsies throughout the colon. This approach is quite different to what we do during screening colonoscopies in patients without IBD. This unique approach for screening and surveillance in patients with IBD was based on the common notion nicely summarized in a 1995 review article that 95% of dysplastic foci occurred in patients in flat mucosa and was essentially invisible and only occasionally visible macroscopically.6 With improved resolution colonoscopes, cables and monitors over the past decade, this notion has changed. More recent data suggest that most dysplasia is visible, not invisible, and the overall yield of random biopsies is low. Even so, other studies show nearly 25% of dysplasia discovered on colonoscopy is from random biopsies and not visible.7 As the need and value of random biopsies is debated, the more relevant question is whether these invisible lesions are truly invisible or simply hard to see. Recent data suggest strategies for enhancing dysplasia detection may be useful for detecting these “invisible” lesions, perhaps obviating the need for random biopsies.

Introduction of enhanced dysplasia detecting techniques such as chromoendoscopy as well as data showing each additional minute of withdrawal time increased the flat dysplasia rate by 3.5% suggests these strategies may help reduce the invisible dysplasia rate even further and potentially eliminate the need for random biopsies. An important take home is that even when the dysplasia is visible, it may not look like a classic polyp. The 1995 review that reported that 95% of dysplasia is not visible endoscopically, also noted that when it is seen, it may be subtle, such as an irregularity, discoloration or nodularity that could be obscured by inflammation. This description of what subtle dysplasia looks like is probably still relevant today. What has changed is that likely what we thought was invisible dysplasia is now at least partly visible with better control of inflammation, technologic improvement of scopes and monitors and better appreciation of subtle findings on colonoscopy.

Thus, besides trying to reduce inflammation as much as possible when performing surveillance, it is important to focus and biopsy anything that may look different than its neighbor or catches one’s attention. If a lesion looks particularly concerning, marking the area with India Ink will be helpful for finding the lesion in the future should the biopsies show dysplasia. Despite this, we must still recognize that lesions can be missed because they can be subtle and blend easily with the surrounding inflammation.

3. Chromoendoscopy but Not Virtual Chromoendoscopy Improves IBD Dysplasia Detection Rate

Chromoendoscopy involves the application of dilute methylene blue or indigo carmine during colonoscopy to the mucosa of the colon with the goal of improving visualization of dysplasia. This is achieved by enhancing contour differences between the lesion and the surrounding mucosa as well as differential uptake of stain between normal and dysplastic tissue. Several studies have now shown this strategy improves detection of dysplasia in IBD patients over white light, particularly when using standard definition colonoscopes. So called “virtual chromoendoscopy” on the other hand is alteration of the image by the processor to create a pseudocolorized image designed to enhance the detection of subtle colonic lesions. These are often proprietary technologies such as narrow band imaging (Olympus) or iscan (Pentax) to name two. However, despite the utility of these technologies to better define lesions, clinical trials have not shown that they improve the detection of dysplastic lesions over white light colonoscopy. Thus, if one wanted to engage in an evidence-based enhanced dysplasia detection technique that contains the word “chromo”, dye needs to be sprayed on the colon.

A recent review on the how to perform chromoendoscopy is a useful reference for those who want to learn the technique.8 It is important that the patient is well prepared to perform chromoendoscopy. The dye is diluted and can be applied via spray catheter or foot pump. Recommended is to exchange the water irrigation with contrast solution if using the foot pump once the cecum is reached. The dye should be applied circumferentially while withdrawing, spraying on the anti-gravity side. Typically, the colon is examined in 20-30 cm segments, once with white light, then reinserting and applying the dye and examining a second time after the dye has been applied. Suspicious areas showed be targeted for biopsies or if resectable, removed endoscopically.

4. Avoid Older Terms like DALM and ALM to Describe and Manage Dysplasia

The traditional description of dysplasia involved such terms such as flat dysplasia, dysplasia associated lesion or mass (DALM), adenoma like lesion or mass (ALM) and adenomatous polyps. The problem with these terms is that the definitions were quite vague. For example, the ALM and adenomatous polyp were often indistinguishable clinically. The difference between the DALM and ALM was a functional one, where the DALM was a lesion that could not be resected endoscopically or biopsies surrounding the lesion showed evidence of dysplasia whereas the ALM could be resected endoscopically or had no dysplasia on biopsies surrounding the lesion. Flat dysplasia also produced semantic problems it was it was not always clear if what was meant was visible lesions that were wider than tall or those not seen visually but detected on random biopsies during colonoscopy. Although there is no formal consensus on the optimal way to describe dysplasia in IBD, consensus is to abandon the use of terms such as DALM, ALM and flat dysplasia for terminology already in use for patients without IBD.

What has been proposed is to first dichotomize dysplasia into visible or invisible dysplasia (the latter detected solely on random biopsies).9 Visible dysplasia should be defined into one of 3 categories of lesions that should be familiar to practicing gastroenterologists: 1) pedunculated (lesion attached to mucosa by a stalk); 2) sessile (lesion not attached to mucosa by stalk, entire based is contiguous); and 3) non-polypoid (lesion <2.5 mm above the mucosa with little or no protrusion above the mucosa. Non-polypoid dysplasia perhaps is the term least used by gastroenterologists but it is easy to define: 2.5mm is the half the height of the cup of a closed biopsy forceps.

Once defied this way, one can apply more standard principles of polyp/dysplasia management that are familiar to most gastroenterologists. For example, when managing dysplastic lesions in patients without IBD (such as a tubular adenoma), the first step in management is to define whether the lesion is discreet and endoscopically resectable either by the gastroenterologist performing the procedure or by someone else employing advanced endoscopic technique. One distinction to note is that in patients with IBD, the disease itself can cause scarring in the underlying mucosa, so lesions may be more difficult to lift and resect than the same lesion in a patient without IBD. If marking the lesion with India Ink, it is helpful to pick the wall opposite the lesion, especially if referring to someone else, as the India Ink itself can cause scarring if injected nearby the lesion. This approach of defining management of visible dysplastic lesions in IBD based on the same principles of endoscopic management in patients without IBD represents a further evolution of managing dysplasia in IBD with less surgery that has been occurring over the past 15-20 years. Even so, it is important to note that this strategy, while reasoned and based on experience and some evidence, has not been validated.

5. Most IBD Patients with Dysplasia Do Not Need Surgery, but Some Do

Two seminal studies published in the late 1990s changed our thinking on the need for surgery on most patients with IBD and visible dysplasia. These studies ushered in the term “ALM” and suggested that these discrete polyps called “ALMs” with no surrounding dysplasia can be managed with polypectomy alone and did not need surgery. Another seminal study published in 2004 demonstrating that most dysplasia (roughly 75%) was visible, further moved the needle that perhaps if the lesion could be seen, even more patients could be eligible for polyp resection. This thinking was in contrast to the thinking just a decade before that most (95%) dysplasia in IBD was invisible and even when visible, appeared to be ill-defined lesions that could not be resected (Table 2).

That being said, the decision of how to manage any dysplastic lesions found on colonoscopy in a patient with IBD has to be individualized based on the appearance of the lesion, resectability of the lesion, degree of symptoms and inflammation and cannot be generalized into a single summary as to whether IBD dysplasia is managed surgically or endoscopically. Despite advances in optics and techniques, the fact is that even in the 2004 article that first observed that most IBD dysplasia was visible, one of 25 of the “invisible” dysplastic lesions were actually a cancer. Among the visible lesions, six of 85 were cancers but only one could be confirmed histologically at colectomy. Table 2 shows how the proportion of patients who may need surgery has changed. The management of invisible low-grade dysplasia (previously called flat) has been controversial, with the most recent 2010 AGA guidelines proposing an insufficient data to provide a recommendation regarding surgery vs. ongoing surveillance.3 The 2015 SCENIC consensus statement recommended performing a colonoscopy with chromoendoscopy in these patients and include extensive random biopsies in the area of interest to at least determine whether the “invisible” lesion can be visualized with dye spray.9

CONCLUSION

The field of inflammatory bowel disease dysplasia is changing and studies suggest advances in reducing CRC risk in IBD likely due to improved control of inflammation (primary prevention) and surveillance colonoscopy (secondary prevention). Despite limitations in data, surveillance colonoscopy is a currently practiced strategy for IBD patients to prevent colon cancer. By following these 5 tips (choosing the right patient for surveillance, focusing on mucosal abnormalities not random biopsies, incorporating chromoendoscopy in the right patient, abandoning older terms to describe dysplasia and knowing that most patients do not need surgery when dysplasia is found but some do) the hope is to simplify and improve our ability to detect and manage dysplasia in patients with IBD and prevent mortality from colorectal cancer.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #22

Understanding the Etiology and Spectrum of Idiopathic Gastroparesis

April 2017 • Volume XLI, Issue 4
Danny J. Avalos,Pratik Naik,Richard W. McCallum

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Gastroparesis is a debilitating disease of delayed gastric emptying (GE) which affects approximately 10 million people in the United States. Diabetes-related and post-surgical gastroparesis are well-known entities, but the majority of patients with gastroparesis have no identifiable etiologies and are labeled as idiopathic (IG). Although post-infectious causation has been implicated in IG, the pathophysiology of IG remains elusive. Vagal nerve impairment, changes in enteric neurons, and depletion of interstitial cells of Cajal have been demonstrated. The diagnosis of IG is based on clinical symptoms and an abnormal scintigraphic gastric emptying study. This article aims to review new discoveries in idiopathic gastroparesis and update entities that may be incorrectly labeled idiopathic gastroparesis.

Danny J. Avalos, MD, GI Fellow, PGY-4, TTUHSC Pratik Naik, MD, GI Motility Fellow, TTUHSC Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

INTRODUCTION

Gastroparesis (GP) is a disease of delayed gastric emptying where mechanical obstruction of the upper gastrointestinal tract has been excluded. Often, disordered gastric emptying is accompanied by post-prandial nausea, vomiting, early satiety, bloating and abdominal pain. Estimated to occur in 10 million (3%) people in the Unites States, gastroparesis can be categorized into diabetic (DG), post-surgical (PSG) and idiopathic (IG). Idiopathic gastroparesis accounts for up to 50-60% of cases and primarily affects females (88%) with an average age of onset of 41 years.1 Case reports and case series have linked an infectious prodrome (gastroenteritis or flu-like symptoms) to IG, and this particular sub-category is termed post-infectious GP. It had previously been reported that post-infectious GP accounts for approximately 21% of all IG cases,2 however, this number will be higher with new data. Also, post-infectious GP patients seem to have a higher likelihood for spontaneous recovery.2

The majority of the data for understanding IG comes from the NIDDK Gastroparesis Clinical Research Consortium (GpCRC), a collaborative effort from experts at a few specialized academic motility centers in the U.S. The consortium has led multiple studies with the aim of improving the understanding of the pathophysiology, clinical presentation, and response to therapy in GP. Symptoms of nausea, vomiting, and abdominal pain have been associated with a poor quality of life among all GP patients.3,4 Data from the NIDDK Gastroparesis Registry revealed that among 159 patients with gastroparesis (107 IG, 52 DG), nausea was the predominant symptom in both groups, vomiting was more common in DG (81% vs. 57% p=0.004),5 and abdominal pain was more common in IG.6 Also, psychological profiles have identified depression along with physical and sexual abuse as present in up to 62% of the female patients with IG.7 These factors contribute to visceral hypersensitivity and could help explain the higher prevalence of abdominal pain in IG. The limited understanding about the pathogenesis in IG has led to a non-tailored approach in the management of symptoms. Additionally, many entities (i.e scleroderma), which can cause delayed GE, may be inappropriately labeled as IG. Knowledge of this evolving field will lead to a more focused approach to treatment. The goal of this article is to review this entity of “idiopathic gastroparesis” while also emphasizing these other diagnoses that may mimic IG.

Methods

Pubmed (MEDLINE) was searched using the MESH and non-MESH search terms: “idiopathic”, “post- infectious”, “autoimmune”, “connective tissue diseases”, “paraneoplastic syndromes”, “eating disorders”, “delayed gastric emptying”, “gastroparesis” and “diagnosis”. This search was complemented by the extensive clinical experience of the Center for Neurogastroenterology and GI Motility at Texas Tech University Medical Center in El Paso.

Pathophysiology

Although the pathophysiology of idiopathic gastroparesis remains unclear, some mechanisms and explanations are evolving (Figure 1). Vagal function and regulation have been shown to be impaired among patients with DG, however, to a lesser extent in IG.8,9 Also, the role of the vagus nerve in ghrelin secretion has been proposed. Ghrelin is released mainly by neuroendocrine cells in the gastric fundus and duodenum and has been suggested to function as an appetite-stimulating hormone acting centrally through vagal afferent pathways.8 Ghrelin also has also been shown to stimulate gastric contractility and improve meal related symptoms and gastric emptying (GE) in IG patients.10

Full thickness gastric biopsies in patients with gastroparesis (compared to matched-controls) revealed that nNOS expression was more frequently decreased in IG than in DG (40% vs 20%). Increased connective tissue stroma, however, was visualized in both IG and DG via electron microscopy.11 Loss of interstitial cells of Cajal (ICC) has been a predominant finding among patients with both DG and IG,11 being present in up to 50% of cases and has been correlated with delayed gastric emptying in DG.12 Interstitial cells of cajal are regarded as the origin of the gastric electric activity and the loss of ICC impairs and disorganizes the electrical signal resulting in reduced peristalsis. Previous studies revealed differences in gastric myoelectrical patterns among patients with IG and non-GP as assessed by electrogastrography (EGG). Idiopathic gastroparesis patients had a more irregular EGG pattern, with reduced 3-cycles-per-minute (cpm) EGG activity, whereas patients with mechanical pyloric outlet obstruction had high-amplitude, regular 3 cpm EGG patterns.13,14 In patients with IG, clinical severity and nausea has been associated with immune-mediated infiltration of the myenteric plexus.15 Evidence of ganglionitis in full thickness gastric biopsies infers a diagnosis of IG. There is also an evolving role of pyloric pathophysiology in the development of GP. Loss of ICC in the pylorus occurs twice as commonly as in the antrum, and fibrosis in pyloric smooth muscle is three times more common than in the antrum on biopsies of patients undergoing gastric electric stimulation with pyloroplasty.16 Therefore, one unifying concept is that gastroparesis has similarities to “achalasia”. In achalasia, there is both denervation of the esophageal body producing loss of peristalsis, in addition to a non-relaxing lower esophageal sphincter (LES) resulting in esophageal obstruction. In GP, there is impairment of the enteric neurons, ICC loss in the smooth muscle of the antrum, and an impaired relaxation/compliance of the pyloric sphincter resulting in retention of a meal. One of these “dual mechanisms” may be more dominant in an individual GP patient, but both need to be considered and addressed when planning therapies.

How to Diagnose IG: Re-visiting the Gastric Emptying (GE) Diagnostic Criteria

Grading for severity of delayed gastric emptying, adopted from the consensus paper of a Joint Report of the Society of Nuclear Medicine and the American Neurogastroenterology and Motility Societies, is based on the percentage of gastric retention at 4 hours. The following grading system has been proposed: grade 1 (mild): 11-20% retention at 4 h; grade 2 (moderate): 21-35% retention at 4 h; grade 3 (severe): 36-50% retention at 4 h; and grade 4 (very severe): >50% retention at 4 h.17 A recent study by the NIDDK GP Research consortium suggests that the severity of gastric retention significantly correlated with the severity of symptoms when there was more than 35% retention of isotope at 4 hours. This correlation was not significant in the large number of patients with retention of 11-34%.18 To readdress normal gastric emptying criteria (since the original “egg meal” dates back 20 years ago), we recently studied the range of gastric emptying in 25 healthy individuals aged to 30 to 70 years, both male and female, with equal distribution for each decade. Four-hour retention values of up to 17% can be observed in asymptomatic healthy volunteers.19 Therefore, in interpreting the current “gold standard” meal for GE, we recommend that gastric retention > 15% at 4 hours should be considered the appropriate criteria to apply the label of “gastroparesis” and not the >10% standard currently used. Hence the term “idiopathic” gastroparesis needs to be applied with more rigorous GE criteria. Patients with symptoms of postprandial distress and normal GE are generally regarded as having functional dyspepsia (FD). There is more attention being directed to the role of impaired fundic accommodation and rapid filling of the antrum in explaining symptoms of early satiety, fullness, abdominal pain and nausea, which may be more dominant in some patients, categorized as having FD.

Pharmacologic Explanation for Delayed GE

Effect of Marijuana on GE

Cannabis has been shown to delay GE in previous studies. In the first study investigating the effect of delta-9-tetrahydrocannabinol (THC) on gastric emptying, smoking THC was shown to significantly delay GE compared to placebo in normal volunteers who did achieve symptoms of being “high”. The mean percentage of retention was significantly greater in the THC group compared to placebo at all times from 30 min to 2 hours after the test meal.20 Chronic (daily) marijuana use has been linked to the newly recognized syndrome of cannabis hyperemesis and patients may be misdiagnosed as having gastroparesis as a cause of vomiting. More recently, use of recreational marijuana has been approved in many states. It is important to take a careful history and stop all marijuana use for at least 72 hours prior to GE being studied.17

Effect of Medications on GE

There are many classes of medications that can slow GE. In this article, we will emphasize the most commonly encountered medications (Table 1).

Opioids are the most commonly associated medication inducing delayed GE. A randomized controlled trial evaluating 75mg of Tapentadol immediate-release (IR) TID or 5mg Oxycodone IR TID vs. placebo revealed a significant delay in GE with narcotics compared to placebo.21 Medications used for the management of hyperglycemia in type 2 diabetics including Pramlintide,22 an amylin analogue, and Exenatide,23 a GLP-1 agonist, have been associated with delayed GE due to inhibition of vagal function.

Proton pump inhibitors can mildly delay GE to solids by impairment of the acid-dependent peptic activity, which interferes with trituration of ingested food.24

Table 1 lists all the classes of medications that should be considered as possibly slowing GE and emphasizes that a detailed social and medication history is paramount when IG is in the differential.

Hypothesized Etiologies for IG

Post-Infectious Gastroparesis

Post-infectious GP has been reported in both pediatric and adult populations and it has been linked to various pathogens. The pathophysiology of post-infectious GP could be neuropathic or myopathic in origin. The proposed mechanism is believed to be due to inflammation, an immune-mediated phenomenon or an exacerbation or unmasking of an underlying dysmotility.25 There is also literature suggesting possible viral mediated damage to the ICC.13

Viral Pathogens Linked to IG

In the pediatric literature, reports have linked rotavirus to IG. Two cases series reported that among children with post-viral GP, positive for rotavirus, all had full recovery of their gastric emptying over 6-24 months.15,26

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) have been linked to gastroparesis. In a large cohort of 143 adult patients with IG, 11 patients were identified with a post viral etiology of which four had antibody titers against CMV and two against EBV, while the remaining five had a clinical history and presentation consistent with viral etiology based on an illness consistent with gastroenteritis.2 Seven patients (age three months to 47 years old) with a viral prodrome prior to development of GP revealed CMV and EBV as culprits in two cases.13 CMV was also linked to GP in an immunosuppressed patient who developed neurological symptoms and delayed gastric emptying with confirmatory CSF PCR positivity for CMV. This patient later had clinical improvement with ganciclovir.27

Enterovirus (EV) has been linked as a possible causative etiology in IG.28 Seventeen adult patients reported having flu-like symptoms or gastroenteritis prior to diagnosis of IG and 11 subjects had immunoperoxidase staining for EV on mucosal gastric biopsies. Nine patients had active EV infection as noted on endoscopic gastric biopsies and eight patients underwent treatment with antivirals and/or immune therapy. Four out of the eight patients treated experienced symptomatic improvement.

Among other viral etiologies, Norwalk virus and Hawaiian virus have been associated with IG in up to 50% of patients thought to be affected with the viruses.29 Varicella-Zoster has also been associated with IG in a setting of a 52 year-old male with Ramsay-Hunt syndrome who developed GP and had symptomatic improvement with metoclopramide.30

A case series of three adolescent female patients also revealed viral gastroenteritis as a possible culprit for GP.25 Viral GP was identified in seven out of 103 GP cases from the Mayo Clinic. Among the seven cases (three male, four female), the mean age was 26.9 years and symptoms experienced prior to onset of GP included, low-grade fever, fatigue, myalgia with or without diarrhea. A mean follow-up of 32.3 months revealed complete resolution of gastroparetic symptoms in five of the seven subjects while the remaining two had significant improvement in symptoms31 suggesting that post-infectious GP appears to have an overall good prognosis. Neither article specified the pathogens, but it was presumed to be viral as per clinical presentation.

Other Pathogens Linked to IG

In an outbreak of 1300 subjects with waterborne Giardia lamblia, 139 continued to have abdominal symptoms after an initial infection. Of this cohort, twenty-two patients who had a negative follow-up stool analysis for Giardia were compared with 19 controls using GE. There was a significant delay in GE among subjects previously infected with Giardiasis, p<0.01.32

Medical Entities that May be Un-recognized and Inappropriately Labeled as “Idiopathic Gastroparesis”

Connective Tissue Disorder

The esophagus, small intestine and colon are commonly affected in patients with systemic sclerosis (SSc).33 Approximately 47-66% of patients with SSc have delayed gastric emptying to solids.33,34 Dyspeptic symptoms such as nausea, vomiting and epigastric fullness are often observed in SSc patients.33 In one study, 80% patients with abnormal esophageal motility also had significantly delayed GE.33 Similarly, delayed GE with liquids was seen via ultrasonography in 20 patients with SSc vs 20 healthy controls.35 It is hypothesized that collagen replacement of the gastric smooth muscle may lead to subsequent stomach hypomotility in SSc.36

Autoimmune Diagnosis

Gastroparesis in patients with myasthenia gravis with subacute autonomic failure shows clinical improvement after administration of an acetylcholinesterase inhibitor.38 In this report seven patients had antibodies against muscle AChR, and three had antibodies against neuronal ganglionic AChRs (all had thymoma). Autoimmune autonomic neuropathy in association with ganglionic neuronal acetylcholine receptor and N-type voltage-gated calcium channel autoantibodies was also reported in a 60 year-old non-diabetic woman with a 15-year history of GP.39 Patients with Sjogren’s syndrome who have serum antimuscarinic antibodies (IgG) can also have delayed GE.37

Demyelinating Diseases

Acute demyelinating disease is a rare cause of GP, but it should be suspected when symptoms of GP are associated with neurological deficits. Antibodies against the water channel protein aquaporin (AQP)-4 can cause a spectrum of inflammatory, demyelinating, central nervous system disorders termed neuromyelitis optica spectrum disorders (NMOSDs) which can present with GI symptoms similar to GP with intractable nausea, vomiting and hiccups. However, AQP4-IgG positive patients have not demonstrated delayed GE.40 In a case report, a 31-year-old female with acute gastroenteritis developed gastroparesis and suffered a cardiac arrest during the hospitalization. A post- mortem autopsy revealed decreased myelinated axons with vacuolar degeneration consistent with Guillain- Barre syndrome.41 Two cases of patients with focal deficits and demyelinating disease, seen on magnetic resonance imaging (MRI), have also been associated with abnormal GES. Both patients improved with intravenous corticosteroids and one of the patients later developed multiple sclerosis.42

Multiple sclerosis (MS) is a demyelinating disease, which damages the brain and spinal cord. Similar to IG, more patients with MS are women. The most common GI complaints reported in MS patients are diarrhea or constipation and dysphagia.43 Previous studies have demonstrated delayed GE in MS patients. In a study of 49 patients with defined MS and 20 controlled subjects, 47.7% demonstrated slow emptying, 34.1% normal and 18.2% had rapid emptying compared with controls.43 In other reports, the complaints reported in MS patient who presented with symptoms of delayed GE were mainly a sense of fullness, nausea, persistent vomiting, recurrent hiccups and gastroesophageal reflux.44 However, there has been no correlation noted between the severity of MS and gastric emptying abnormalities.

Paraneoplastic Syndrome

Paraneoplastic syndrome can be manifested as esophageal dysmotility (pseudoachalasia), gastroparesis, intestinal pseudo-obstruction or constipation.45 Factors related to cachexia have been theorized as an explanation for paraneoplastic syndrome. Inflammatory lymphocytic and plasma cell infiltrate of the myenteric plexus as well as loss of ganglion cells can be seen on full thickness biopsy in patients with paraneoplastic dysmotility of the GI tract.45

Gastroparesis was reported to be the most common paraneoplastic syndrome associated with type 1 antineuronal nuclear (ANNA-1, also called anti-Hu) antibodies, and small cell lung cancer (SCLC) of the lung is the most common tumor expressing this antibody.45 Plasmapharesis was effective in overcoming the antibodies. The second most common antibody in paraneoplastic syndrome and GP is the P/Q-type calcium channel antibodies, which are predominately seen in patients with Lambert Eaton myasthenic syndrome (LEMS) in association with SCLC.46 Patients with LEMS can present with proximal muscle weakness, depressed tendon reflexes, post-tetanic potentiation and autonomic changes, which can be similar to that of myasthenia gravis. Similarly, a ganglionic acetylcholine receptor antibody has been associated with GP in a patient with bladder cancer but also in patients with no underlying cancer.47

Pancreatic cancer has also been associated with GP. A cohort of 15 patients with pancreatic carcinoma without invasion or obstruction revealed that nine (60%) patients had delayed solid-food GE. Symptoms of nausea and/or vomiting were more frequent among patients with delayed GE as opposed to those with normal GE.48 Other tumors that have been linked with delayed gastric emptying include cholangiocarcinoma,49 as well as intestinal50 and retroperitoneal leiomyosarcoma.51 In the two cases where leiomyosarcoma was linked to delayed GE, both patients had resolution of symptoms after tumor resection.

CNS Degenerative Diseases

Patients with Parkinson’s disease (PD) have been noted to have delayed gastric emptying to solids.52 In a randomized study, 80 patients with untreated PD were compared to 40 healthy controls with solid or liquid gastric emptying. A total of 88% of PD patients had delayed GE with solids and 38% with liquids. Abnormal gastric myoelectrical activity in untreated Parkinson’s disease may be responsible for delayed GE.53 Lewy bodies have also been identified in the smooth muscle and enteric neurons of Parkinson’s disease patients.54 In an animal study, 6-hydroxy-dopamine (6-OHDO) was unilaterally injected into the substantia nigra pars compacta of mice. The mice developed delayed gastric emptying four weeks after a 6-OHDO injection, as measured by a [13C]-octanoic acid breath test. Thus, the authors postulated a neurofunctional and neuroanatomical alteration of the brain-gut axis as a potential etiology for delayed GE in PD.55

Dopamine agonists used in the treatment of PD have been regarded as being a risk for delaying GE. However, treatment with the dopamine agonist as a transdermal patch, rotigotine, has recently shown improvement in gastric emptying.56

Functional Dyspepsia

Approximately 40% of patients with the working diagnosis of functional dyspepsia (FD) may have delayed GE as the explanation for their symptoms.57 Idiopathic gastroparesis patients are more likely to have frequent nausea and vomiting, whereas FD patients have postprandial distress syndrome manifested by early satiety and abdominal discomfort. A meta-analysis of 17 studies with 868 dyspectic subjects and 397 controls revealed that GE was delayed with a relative risk of 1.46 (CI 1.23-1.69).57 Recent reports of duodenal eosinophilia in a subgroup of dyspepsia patients may be another marker for separating FD from GP where eosinophilia in the duodenum was infrequent among the latter group.58

Gastroesophageal Reflux

Delayed GE has been reported in 28 to 56% of the patients with gastroesophageal reflux (GERD) and is a co-existing entity, which can exacerbate GERD symptoms.59 Theoretically, the slow GE induces gastric distention, which increases the frequency of transient lower esophageal sphincter relaxation increasing GERD. A gastric emptying study should be considered in patients whose heartburn is resolved with anti-reflux medication but who continue to report persistent nocturnal regurgitation.

Anorexia Nervosa/Bulimia

Anorexia and bulimia have been associated with dyspeptic symptoms and delayed gastric emptying. In a study of 16 female patients with anorexia nervosa, GE of solid food phase was significantly delayed in 80% of patients.60 In this study, patients with anorexia nervosa were observed to have better tolerance to liquid diet compared to solid meals. Patients with bulimia have had conflicting results. Two studies reported normal GE to solids and liquids,61,62 however, a cohort of female patients with bulimia revealed delayed GE in 38% of the patients.63

Anorexia nervosa in childhood or early adulthood results in an unused or atrophic gastric emptying function, where despite subsequent improvement of eating habits, it does not lead to recovery of the “gastric atrophy.” In another scenario, some patients may still be “closet anorexics” and have hidden their eating behaviors. Some important clues suggesting an eating disorder are excessive dental caries, finger excoriations and unexplained hypokalemia. Another possible explanation for delayed GE could be secondary to endocrine dysfunction (i.e hypoadrenalism) observed in patients with eating disorders.

Celiac Axis Injury or Compression

Compression or injury to the celiac plexus ganglion can affect parasympathetic signaling to the stomach, resulting in loss of myenteric coordination. Compression of the celiac axis by a fibrous band (the median arcuate ligament) connecting the diaphragmatic crura is called median arcuate ligament syndrome (MALS) which is characterized by abdominal pain, nausea and vomiting. A case report of a patient presenting with postprandial epigastric pain, weight loss, gastroparesis and gastric dysrhythmias was diagnosed with MALS and had significant improvement of symptoms and GE after surgical decompression of the celiac axis. The patient was able to return to a full diet within four weeks without nausea or vomiting.64 This entity is not explained by vascular insufficiency but by compression of the celiac ganglion via the the fibrous ligament. Clinical clues include nausea, vomiting and upper abdominal pain which is out of proportion to abdominal examination

Hypermobility Syndrome

Joint hypermobility syndrome (JHS), a type of Ehlers- Danlos Syndrome (EDS) (formally called type III), is a new addition to an association with GI symptoms. Patients with JHS have hypermobility of the joints, skin hyper extensibility and easy brushing. In a case- controlled study of the 336 patients with functional gastrointestinal disorder (FGID), 39% were also diagnosed with JHS. More specifically 51% of the FGID patients whose predominant symptom was postprandial distress were diagnosed with JHS.65 Postural orthosthetic tachycardia syndrome (POTS), caused by dysfunctional autonomic control mechanism, is accompanied by JHS in up to 60% of patients.66 In a large cohort study of 163 patients with POTS, 34% had normal, 18% has delayed and 48% had rapid GE.67 In JHS patients, autonomic dysfunction and decrease in compliance of the gut wall may influence GE. Review of literature suggests that rapid gastric is more common in JHS patient with POTS but in absence of POTS, occurrence of rapid and delayed GE were similar.68

Miscellaneous Causes for Delayed GE

Cystic fibrosis (CF) can be associated with GI dysmotility including GP, GERD and chronic constipation. The average life span of patients with CF who live to adulthood is 37 years. In a systemic review, patients with CF had a high frequency of GP (38%) and it was more prevalent among patients older than 18 years of age.69 The co-existence of GP and CF may pose significant nutritional challenges.

Cases of GP in patients receiving abdominal, pelvic and total spine radiation have also been documented.70 There is also a report of GP in patients who received high dose chemotherapy and stem cell transplant.71 Post- chemotherapy treatment GP is rare and pathophysiology behind the process is not well established but could relate to being part of the paraneoplastic syndrome or neuropathy from the chemotherapy agent. 1

Delayed solid emptying is also noted in atrophic gastritis with or without pernicious anemia,72 which is explained, by a combination of achlorhydria and thinning of smooth muscle. Other diseases associated with delayed GE include mastocytosis73 and eosinophilic gastroenteritis.74

TAKE HOME POINTS

A wide spectrum of contributing factors and unappreciated entities can result in the label of “idiopathic gastroparesis”. Idiopathic gastroparesis is also a term that may be overused as the etiology for unexplained upper gastrointestinal symptoms. The diagnosis of IG must be rigorously made with particular attention to the interpretation of a scintigraphic GE study, where abnormal should be >15% retention at 4 hours, not the current >10%. Medications, specifically opioids and marijuana, are key factors to consider in interpreting a gastric emptying study. This article helps the reader gather enough data to differentiate idiopathic gastroparesis from other diagnoses while at the same time emphasizing the importance of a thorough evaluation of the patients’ history for factors that can have a long term effect on gastric motility and present as gastroparesis. In the future, the diagnostic approach will benefit from a non-surgical way of obtaining gastric smooth muscle tissue to examine enteric neurons, and ICC, which will be achieved by endoscopic ultrasound- guided biopsies of gastric antrum smooth muscle. Patients with suspected post-infectious gastroparesis appear to have an overall good chance of recovery. Idiopathic gastroparesis, the most common subset of gastroparesis patients, remains a challenging diagnostic and clinical entity. We hope this article will give you new expertise in addressing this in your practices.

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Nutrition Issues In Gastroenterology, Series #162

Protein Losing Enteropathy: Diagnosis and Management

April 2017 • Volume XLI, Issue 4
Andrew P. Copland,John K. DiBaise

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Protein losing enteropathy (PLE) is an uncommon etiology of hypoproteinemia. It is caused by protein loss from compromised gastrointestinal (GI) mucosa as a result of GI mucosal diseases, GI tract infections, as well as from disruptions of venous and lymphatic outflow. The prevalence of PLE is poorly understood given the wide variety of causes of both hypoalbuminemia and PLE, and due to a lack of systematic screening. The evaluation of a potential PLE patient includes a careful assessment for alternative causes of hypoalbuminemia and a measurement of GI tract protein loss. This review provides the clinician with diagnostic criteria, as well as management and nutrition support options.

Andrew P. Copland, MD1 John K. DiBaise, MD2 1Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA 2Division of Gastroenterology and Hepatology, Mayo Clinic in Arizona, Scottsdale, AZ

INTRODUCTION

Protein-losing enteropathy (PLE), sometimes referred to as protein-losing gastroenteropathy, is an unusual cause of hypoproteinemia and is characterized by the shedding of large quantities of protein from the gastrointestinal (GI) mucosa. PLE may result from a wide variety of etiologies and can be both a diagnostic and therapeutic challenge to the practicing gastroenterologist. The clinical presentation of PLE may also be complicated by micronutrient deficiencies related to the underlying etiology of the PLE. In some cases, we have noted significant vitamin deficiencies and deficiency of essential fatty acids complicating the care of these patients. Through the use of a case illustration, we will explore a practical approach to the evaluation and management of PLE.

In early 2016, a 51 year-old woman presented to the GI clinic upon referral by a hematologist because of the development of progressive hypoalbuminemia (albumin 2.6 g/dL) which had been identified approximately 1 year earlier. She described one normal appearing stool per day, denied any GI complaints, and her physical examination was entirely normal.

PLE is generally considered to be a rare condition; however, given a lack of systematic screening and a wide variety of causes of hypoalbuminemia, its prevalence is poorly understood. There are robust data describing an incidence of up to 18% among survivors of the Fontan procedure, used as treatment of the univentricular congenital heart; however, data are much more limited for other causes of PLE.1 A 2-3% prevalence of PLE has been reported among Asian patients with systemic lupus erythematosus (SLE).2 In a study of 24 patients with ileal Crohn’s disease in clinical remission, all had laboratory evidence of PLE (although none had clinical signs), suggesting that the prevalence of PLE may be significantly underrecognized.3 Similarly, in a study from 1975, 22% of 55 patients with primary lymphedema who were screened for PLE were found to have evidence of protein wasting from the GI tract.4

Despite the poor understanding of its prevalence, PLE should be a consideration in the evaluation of patients who present with moderate to severe hypoalbuminemia (serum albumin <3.0 g/dL), particularly those who present with edema. Although some patients with PLE present with severe GI symptoms such as diarrhea, which can take on a secretory character, it is important to recognize that not all patients suffering from PLE will exhibit overt GI symptoms. In fact, the key clinical characteristic of PLE is symptomatic hypoalbuminemia which manifests most commonly as edema. Other clinical manifestations generally reflect the underlying disease responsible for PLE.

Pathophysiology

The protein loss in the bowel typically results in serum albumin levels <3.0 g/dL, and frequently <2.0 g/dL. In the normal GI tract, only 1-2% of total daily protein is lost through active intestinal secretions and mucosal turnover.5 This is significantly different from the dramatic protein losses from the GI tract seen in PLE, which can result in daily loss of as much as 60% of the total serum protein. 6 Because albumin contributes about 80% of the total colloidal osmotic effect of human serum due to its oncotic effect and affinity for sodium ions, loss of serum albumin results in third-spacing of fluid and generally manifests clinically as peripheral edema, ascites, and pleural effusions.7 In addition to symptomatic hypoalbuminemia, patients presenting with PLE may be at increased risk of infection and thrombosis due to concomitant stool loss of serum immunoglobulins and key anticoagulant proteins respectively, although neither occurs commonly.

In the context of increased serum protein loss, the body will attempt to compensate by increasing protein synthesis. As such, serum levels of rapid turnover proteins including prealbumin, immunoglobulin E (IgE), and insulin may remain normal.8 In contrast, insufficient compensatory protein production and low serum level is more often seen with slower turnover proteins such as albumin, ceruloplasmin, fibrinogen, transferrin, and immunoglobulins (other than IgE), as the body has a less robust capacity to increase daily production.5 Albumin in particular is a slow turnover protein with a half-life of about 25 days; there is also evidence that the liver is unable to fully compensate for sustained albumin losses.7 Decreased serum levels of lipids and trace elements have also been reported in PLE, as has the presence of lymphopenia, particularly in the setting of lymphatic obstruction or malnutrition. The reduction of serum proteins other than albumin seldom causes clinically significant problems.

Her past medical history was notable for remote peptic ulcer disease, hyperlipidemia, seasonal allergies and persistent unexplained peripheral eosinophilia first discovered in 2010. In 1989, she underwent a vagotomy and pyloroplasty for gastric outlet obstruction due to peptic ulcer disease. Extensive evaluations of the eosinophilia by specialists in infectious diseases, hematology, allergy, immunology, and rheumatology were unsuccessful in identifying an etiology.

Alternative causes of hypoalbuminemia

Other causes of hypoalbuminemia are diverse and warrant careful thought when evaluating the hypoalbuminemic patient. In particular, fluid overload (e.g., congestive heart failure), reduced protein synthesis (e.g., chronic liver disease), and other sources of serum protein losses (e.g., nephrotic syndrome) are important to consider. This evaluation should include a careful history and physical examination, as well as standard evaluations of other causes of hypoalbuminemia noted in Table 1.

A diagnostic evaluation revealed no evidence of chronic liver disease, nephrotic syndrome or congestive heart failure. Alpha-1-antritrypsin clearance was found to be 341 mL/24 hours (normal, < 27 mL/24 hr), consistent with PLE.

Testing to Confirm a Diagnosis of PLE

The primary diagnostic test for PLE is stool testing for the presence of alpha-1-antritrypsin (A1AT) (Table 2). A1AT is a protein that suffers minimal degradation or active secretion in the GI tract and is of similar molecular weight as albumin. By measuring A1AT levels in both serum and a 24-hour stool collection, A1AT clearance can be calculated as follows:

A1AT clearance = [(mL Stool) x (stool A1AT mg/ dL)] / [serum A1AT mg/dL]

An elevated A1AT clearance >27 mL/day reflects a general state of GI protein loss and has a sensitivity of approximately 80%.7 Diarrhea from any cause, however, results in some obligate A1AT loss and, thus, a higher threshold (>56 mL/day) may be required for the diagnosis of PLE in this situation.9,10 A1AT is also sensitive to degradation by acid so, in the setting of a hypersecretory state, this test is optimally performed while the patient is receiving acid suppression.11 Finally, A1AT testing of a spot stool specimen may also show elevated levels in PLE, but this is a less sensitive approach and is not recommended in the initial diagnosis.10 Use of a random stool A1AT level coupled with serum A1AT level, however, may serve as a convenient surveillance method for patients with known PLE undergoing treatment or in remission.

There are a number of other methods to search for protein loss in the GI tract, albeit none as widely available or as safe as the A1AT clearance. Historically, the gold standard test for PLE has been the fecal excretion of 51Cr labelled albumin, which requires collection of stool for a minimum of 4 days.7 It is not only challenging for patients to complete a 4-day stool collection but it exposes them to radiation and it is not widely available. The 51Cr-albumin clearance may be useful when there is a high clinical suspicion in the context of a negative A1AT clearance given its higher sensitivity. An alternative is technetium 99m-labelled human serum albumin (HSA) scintigraphy. This test has demonstrated superior sensitivity and negative predictive value compared to A1AT clearance for the diagnosis of PLE and has the added benefit of not requiring a prolonged stool collection.12 These tests may also be used to monitor response to treatment.

Upper endoscopy was subsequently performed and was notable for patchy gastric erythema with an atrophic appearance to the stomach. Biopsies from the second portion of the duodenum demonstrated patchy eosinophilia while biopsies from the duodenal bulb were normal. Random biopsies from the stomach showed marked eosinophilia without other abnormalities (Figure 1). Based on the peripheral eosinophilia and presence of eosinophils on the biopsy, the patient was suspected to have eosinophilic gastroenteritis. Interestingly, in 2010, she had undergone upper endoscopy and colonoscopy to evaluate iron deficiency anemia. While both examinations were grossly normal, random biopsies from the stomach revealed a similar intense eosinophilic inflammatory infiltrate throughout the mucosa and submucosa. Biopsies from the duodenum, terminal ileum and colon were normal.

Evaluating Confirmed PLE

When a diagnosis of PLE has been determined, additional testing is necessary in order to identify the underlying cause and help direct treatment. PLE is associated with a diverse set of diseases often affecting multiple organ systems and can be divided into GI and non-GI causes (Table 3). GI sources can be further divided into erosive and nonerosive diseases of the bowel that result in protein loss across the mucosal membrane of the intestine and are detailed in Table 3.

Circulatory dysfunction from cardiac pathology such as congestive heart failure (CHF), constrictive pericarditis, and congenital heart disease can lead to PLE. The most common cardiac cause of PLE occurs in adults with congenital heart disease, a functional single ventricle, treated as a child with a palliative Fontan operation.1 Post-Fontan patients make up the largest cohort of patients with PLE described in the literature.

PLE is associated with a significant morbidity and mortality depending upon the underlying cause. The five-year mortality after diagnosis of PLE in the setting of a Fontan procedure approaches 50%; however, recent data suggest that advances in our understanding of the disease may have improved this rather dismal outlook.13 While data on morbidity and mortality associated with PLE related to other causes are more limited, malnutrition, volume overload, thrombophilia, and secondary immunodeficiency, likely have a significant impact on long-term outcomes.

Because the management of PLE is closely tied to treating the underlying disease, when PLE is identified, a thorough evaluation should be undertaken to better characterize the state of the GI tract mucosa, lymphatic system, and cardiovascular system. This is best approached through upper and lower GI endoscopy with mucosal biopsies as well as infectious studies (focusing on chronic intestinal infections). If conventional endoscopy does not yield a diagnosis, video capsule endoscopy or small bowel enteroscopy have been shown to be useful in patients with known PLE.14 Cross-sectional imaging of the abdomen and pelvis, echocardiogram, lymphatic/hematologic tests and, sometimes, diagnostic laparoscopy may also be useful depending on the clinical presentation.

Mechanisms Causing PLE

As our understanding of PLE has improved, it has become increasingly clear that a common link between the various etiologies of the disease involves injury to, or breakdown of, the GI epithelium causing increased permeability. Conceptually, this pathology is clear when considering PLE caused by mucosal diseases such as inflammatory bowel disease, eosinophilic gastroenteritis, and microscopic colitis, for example. Poor lymphatic drainage from congenital defects or from significant lymphatic obstruction may cause loss of lymphatic fluid into the GI tract through direct hydrostatic forces.15 Although the mechanism responsible for PLE in systemic autoimmune disease is unclear, it has been hypothesized that it results from mucosal or capillary inflammation caused by:

  • 1. local vascular injury mediated by complement or vasculitis
  • 2. lymphatic damage through mesenteric inflammation, or
  • 3. increased endothelial permeability through the effect of inflammatory cytokines.16

The cause of PLE associated with cardiovascular diseases such as CHF and the Fontan procedure is generally considered to be increased hydrostatic pressure from venous hypertension which, at least in part, results in loss of protein into the GI tract.1 Interestingly, these patients do not have significantly elevated venous hypertension relative to similar patients without PLE making the exact pathophysiologic process less clear.1 Some of these patients seem to respond to treatments based at the level of the mucosal membrane, implying that perhaps mucosal injury is again a primary root cause. Some hypothesize that hemodynamic changes associated with the Fontan procedure result in increased mesenteric vascular resistance as a compensatory mechanism to poor cardiac output.17 This may in turn damage the mucosal epithelium, increase permeability and engorge intestinal lymphatics with an appearance histologically similar to congenital intestinal lymphangiectasia. There are also data to suggest that patients with univentricular-type congenital heart disease may have increased protein loss in the GI tract prior to the Fontan procedure; this may reflect either a response to the initial circulatory dysfunction of the congenital heart disease or concurrent congenital malformation of some component of the GI tract itself.18 Others have attempted to strengthen the argument for mucosal injury by demonstrating that patients who have undergone a Fontan procedure typically have elevated inflammatory markers.

The patient was placed on prednisone for suspected eosinophilic gastroenteritis with rapid normalization of her serum albumin and eosinophils and more gradual normalization of the A1AT clearance. With weaning of the prednisone, an increase in peripheral eosinophils and decrease in albumin occurred prompting initiation of oral cromolyn and budesonide. Thereafter, she was able to eliminate prednisone use. Repeat upper endoscopy approximately one year later was normal including duodenal and gastric biopsies. Interestingly, biopsies from the upper esophagus demonstrated marked eosinophilia consistent with eosinophilic esophagitis. Notably, she denied dysphagia or any other esophageal symptoms.

Management of PLE

Because PLE is a rare disease with a variety of seemingly disparate causes, there are limited data on its optimal treatment. As such, no single treatment reliably improves PLE in all patients. A core principle is to treat the underlying disease which, if successful, should generally result in improvement in the PLE. Fortunately, most causes of PLE can be readily diagnosed and treated. Examples might include optimization of the management of eosinophilic gastroenteritis as demonstrated in our case illustration, or fenestration of the Fontan heart to improve cardiac output.20

A number of PLE-specific strategies have been described and include dietary, pharmacological or surgical interventions. No controlled studies, however, have been performed to demonstrate the utility of these approaches. It is also important to recognize that there is often a substantial delay in clinical response to treatment of PLE, which may take months to display a measurable response. Nutritional strategies focusing on protein deficiency are important. A high protein diet is recommended in patients with PLE and may require significantly greater protein intake (2.0-3.0 g/ kg/day) than normal (0.6-0.8 g/kg/day) to remain in a positive nitrogen balance.6 In patients with associated fat malabsorption, primary or secondary intestinal lymphangiectasia or other lymphatic disorders causing PLE, a lowering of fat intake may decrease pressure on the lymphatics and limit protein leakage.15 To replace these lost fats, medium-chain triglycerides can be tried as these provide a source of energy rich fats and are absorbed largely via the portal vein rather than the lymphatics.15 However if a very low fat diet is used > 3 weeks, a source of essential fatty acids will be necessary and fat soluble vitamins may need to be monitored.21 If oral intake is inadequate, enteral feedings should be considered. If fat malabsorption has been demonstrated based on a quantitative fecal fat collection with fat ingested or infused enterally, then a semi-elemental or elemental product should be used. If the patient fails enteral, then parenteral will be necessary.

Although dietary modification may not produce obvious benefit in terms of symptoms or degree of protein wasting, the optimization of the PLE patient’s nutritional status is important to the success of other therapies and the patient’s overall outcome.

Direct replacement of serum albumin by infusion is not a useful long-term strategy as it provides only short-term benefit, is expensive, and does not reverse the underlying pathophysiology. In the acute setting, albumin infusion may help patients suffering from severe third-spacing of fluid due to marked hypoalbuminemia as a bridge to more durable therapies.22

Supportive measures to avoid complications resulting from fluid retention contribute meaningfully to PLE patients’ quality of life. Use of compression stockings may help decrease edema and improve functional status. Careful skin care along with edema management is important to avoid pressure ulcerations and other complications of skin breakdown.

Although there are a number of anecdotal case reports and small case series of medical therapies for patients with specific causes of PLE, there are no high quality randomized controlled trials of any therapy in PLE (see Table 4). In some cases, a surgical approach to the primary underlying GI pathology is necessary. In inflammatory bowel disease, for example, this might result in resection of active bowel affected. Gastrectomy may prove curative for patients with Ménétrier’s disease.

Practical approach to PLE

Given the rarity of the PLE and the lack of rigorous supportive data, the treatment of PLE can be a puzzle to the clinician. The initial step in the evaluation of hypoalbuminemia is to exclude other, more common, causes such as liver and renal diseases. When concern over PLE remains, the A1AT clearance test is recommended as the test of choice given its reliability, relative inexpense, and wide availability. After a diagnosis of PLE has been made, the following approach is suggested:

  • 1. Aggressive pursuit to identify the underlying disease responsible for PLE and treat accordingly while encouraging a high protein diet and supportive measures for fluid retention when present. A low-fat diet and supplementation with medium chain triglyceride supplementation should be considered on an individual basis. Monitoring and treatment of any associated malnutrition and/or micronutrient deficiencies, when present, is also important. In certain conditions where severe symptoms prevent adequate oral intake, occasionally use of either enteral or parenteral support may be needed.
  • 2. If cardiac disease is an underlying etiology, addition of diuretic regimen including spironolactone should be considered. The chronic use of diuretics in other settings, while commonly attempted, is otherwise generally discouraged as is the long-term use of intermittent albumin infusions. The use of other “heart failure” medications in order to optimize cardiac output in those with cardiac etiologies of PLE may also be pursued.
  • 3. A trial of pharmacological agents such as corticosteroids, heparin, and octreotide may be considered in patients who have not responded to other measures, but should not be considered primary therapeutic agents for PLE. The use of cetuximab and everolimus should be considered based upon its reported use in relevant underlying diseases. If a trial of budesonide 9mg daily results in clinical improvement, a gradual taper over several months is recommended, recognizing that recurrence is common after discontinuation. Subcutaneous heparin or octreotide may be used in combination with oral or intravenous corticosteroids.
  • 4. Periodic monitoring of the degree of PLE is advised, for example, by using A1AT clearance, after treatment is initiated. Similarly, periodically monitoring the serum albumin level is recommended with the assessment of other serum chemistries and micronutrients on a case-by-case basis.

CONCLUSION

The patient described in our case illustration represents a typical case of PLE with a GI etiology with the exception of an absence of edema. It highlights the need to recognize PLE as a cause of unexplained hypoalbuminemia even in the absence of GI symptoms or evidence of fluid retention. PLE can occur in the context of a myriad of diseases ranging from primary GI mucosal disorders, to malignancies, to lymphatic disorders, to congenital heart disease. Diagnosis is most commonly confirmed by the A1AT clearance test. The care of the patient with PLE can be challenging and often requires a multidisciplinary approach. While the evidence regarding the management of PLE is limited, treatment primarily focuses of the underlying disease with the addition of supportive measures to manage complications such as edema.

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Frontiers In Endoscopy, Series #35

Endoscopic Ultrasound Guided Gastroenterostomy for the Treatment of Gastroduodenal Outlet Obstruction

April 2017 • Volume XLI, Issue 4
Emmanuel Coronel,Uzma D. Siddiqui

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Here we discuss EUS-guided gastroenterostomy (EUS-GE) as a novel, minimally invasive technique that can be used to palliate the symptoms of gastroduodenal outlet obstruction due to benign or malignant conditions. Due to the risk for serious adverse events, no current standardized technique and limited published data, this endoscopic technique should only be undertaken by experienced endosonographers. Early results show promise in the treatment of gastric outlet obstruction.

Emmanuel Coronel, MD Uzma D. Siddiqui, MD, FASGE, Center for Endoscopic Research and Therapeutics (CERT), Chicago, IL

BACKGROUND

The term gastric outlet obstruction has been used broadly to define any mechanical obstruction impairing gastric emptying into the small bowel. The area of obstruction can be in the distal stomach or proximal duodenum, and can be due to an intraluminal lesion or from extrinsic compression, most commonly from malignancy. Patients often present with early satiety, nausea, vomiting (usually undigested food contents) and weight loss. Upper endoscopy and cross- sectional imaging, such as an upper gastrointestinal series with oral contrast or a contrast-enhanced computerized tomography (CT), are necessary not just to confirm the diagnosis but also to evaluate the location and severity of the obstruction. Interestingly, until the 1970?s, the most common cause of gastric outlet obstruction was pyloric stenosis associated with peptic ulcer disease. Since the introduction of effective acid suppressive medications and the identification of Helicobacter pylori as one of the main drivers of peptic ulcer disease, severe peptic stricture has become rare. Currently, the most common etiology of gastric outlet obstruction has become pancreatic cancer.1 However, although less common, gastric outlet obstruction can arise from duodenal compression caused by chronic pancreatitis.

Many patients with gastric outlet obstruction are not ideal candidates for surgical resection of the obstructing tumor due to the presence of advanced malignancy. Therefore, these patients are managed with palliative interventions such as surgery (open or laparoscopic gastroenterostomy) or endoscopy, traditionally via enteric stent placement. These patients are frequently debilitated and have a poor performance status and while surgery, when successful, offers better long term outcomes it is associated with much higher rates of morbidity and mortality when compared to minimally invasive interventions such as endoscopic stenting. Endoscopic stenting is safe and effective for symptom palliation in gastroduodenal outlet obstruction. In a retrospective study comparing its outcomes against surgery, endoscopic stenting had significantly less complications and patients had shorter hospitals stays but had a higher re-intervention rate and overall charges.2 Enteral stents are designed for patients with malignancy and may not be ideal for use in benign conditions.3

Endoscopic ultrasound (EUS) was initially utilized as a diagnostic modality in pancreatic diseases dating back to the 1980?s where a radial echoendoscope allowed detailed imaging to be obtained due to scope proximity to the pancreas while sitting in the gastrointestinal tract. In the 1990?s, the linear echoendoscope with an accessory channel was developed which allowed for therapeutic interventions. This included pancreatic sampling (fine needle aspiration and fine needle biopsy) and drainage of multiple types of lesions (pseudocysts, bile ducts, and pancreatic ducts).

More recently, with the advent of lumen apposing metal stents (LAMS), EUS guided placement has been used in the creation of luminal anastomoses. The idea of creating a luminal anastomosis between the stomach and small bowel (EUS-guided gastroenterostomy) using a stent was initially developed in animals. In 2012, Binmoeller and Shah showcased the results of this technique using a porcine model.4 The procedure was performed using an anchor wire to appose the lumen of the small bowel to the stomach and a biflanged lumen apposing metal stent (LAMS) was deployed under ultrasound guidance to create the anastomosis. The procedure was technically successful in all four animals without complications. Another animal study from Japan performed by Itoi et al.5 showed similar results with a successful creation of a gastroenteric anastomosis and no adverse events. In this study, the authors used different devices such as a novel double balloon enteric tube to access the small bowel and a different lumen apposing metal stent.

In the United States, a cautery-enhanced (CE) LAMS system allows for direct puncture through the stomach and into the small bowel and obviates the need for tract dilation prior to stent deployment. Furthermore, the single-step access to the small bowel may minimize the chance for separation between the stomach and small bowel. The biphalanged design of the stent reduces the risk of migration and we would advocate using the 15mm diameter size. However, the use of CE-LAMS for gastroenterostomy is an off-label indication.

Endoscopic Technique

EUS-guided gastroenterostomy (EUS-GE) using LAMS was developed as a way to bypass the obstructed proximal duodenum with direct placement of the stent between the stomach and more distal duodenum or proximal jejunum. This new endoscopic technique continues to evolve as endosonographers gain more clinical experience and as more devices are developed for the creation of endoscopic anastomosis. There is no ?ideal method? of how to perform this procedure and the technique itself has multiple steps that require an expert operator when performing this procedure.

The basic principles include filling the small bowel with contrast to distend it for better apposition with the gastric wall, puncture into the small bowel, and then stent deployment with the distal flange in the small bowel and the proximal flange in the stomach. This can be performed using different approaches.

The initial access can be performed by using a 19-gauge needle and advancing a guidewire into the small intestine or can be performed directly ?freestyle? using the cautery enhanced (CE) LAMS delivery system.

It is of utmost importance to ensure adequate visualization and distention of the small bowel prior to puncture. Depending on the degree of lumen obstruction, every effort should be made to infuse a large volume of dilute contrast into the small bowel. Small amounts of methylene blue can be added to the diluted contrast to help confirm appropriate access after stent deployment. A case series from Japan used a double balloon enteric tube to access the small bowel and distend the bowel distal to the ligament of treitz.6 In two other case series the visualization of the small bowel was performed using biliary or luminal dilation balloons advanced over a guidewire under fluoroscopic guidance.7,8 In this approach, the balloon in the small bowel can serve as target for the 19-gauge needle to puncture. Our preference when using the balloon- assisted technique is the longer length dilation balloons since they provide a larger target for needle puncture.

One major pitfall in this technique is the difficulty in obtaining reliable apposition of the small bowel wall to the gastric wall to prevent misdeployment of the stent into the peritoneum. Currently available LAMS have a 1cm length and therefore the walls must be in close proximity for proper deployment. Some endoscopists theorize that once the small bowel is punctured with the 19-gauge needle and guidewire is passed, it may push the small bowel away from the stomach. Therefore, they advocate for the direct puncture technique using CE-LAMS. Meanwhile, puncture using a 19-gauge needle and passage of a guidewire over which CE- LAMS can be passed allows maintenance of access and potential for ?rescue? placement of a longer fully covered biliary stent to serve as a bridge in cases of LAMS misdeployment.8

Careful stent deployment is critical. In our experience, applying gentle traction is useful to ensure appropriate deployment of the proximal phalange, but care must be taken not to apply too much traction that can cause migration of the distal flange out of the small bowel and into the peritoneum. Once the LAMS has been deployed, careful balloon dilation of the stent lumen can be performed. We suggest dilating to just below the diameter of the stent (i.e. 12mm if 15mm LAMS used). The anastomosis created by the stent can be seen endoscopically and by fluoroscopy. Contrast can also be seen passing through the LAMS from the small bowel and into the stomach under fluoroscopy when placement is correct.

To help illustrate this technique we have added a series of figures on an EUS-GE performed at our institution in a patient with severe gastroduodenal outlet obstruction due to chronic calcific pancreatitis. (Figures 1-6.) The patient has previously had a metal biliary stent placed at an outside hospital for a benign biliary stricture and jaundice. In our case, we used the dilation balloon over a guidewire technique. First, we injected copious amounts of dilute contrast into the small bowel and advanced an 0.035mm guidewire under fluoroscopic and endoscopic guidance (Figure 2). After removing the endoscope, a 20-mm through the scope dilation balloon was passed over the guidewire under fluoroscopic guidance and inflated with contrast. Next, the EUS linear scope was passed down and the dilation balloon was visualized in the small bowel with the scope tip in the stomach (Figure 3). We then used a 19-gauge needle to puncture the balloon in the small bowel and advanced a second 0.035 guidewire deeper into the small bowel. The needle was then exchanged for a 15mm CE-LAMS that was deployed successfully. (Figures 4-6). Finally, the LAMS was dilated using a 12mm balloon allowing contrast from the small bowel to enter the stomach.

Our patient was started on a full liquid diet the next day and then advanced to a low residue diet. He was discharged 48 hours after the procedure, gained 40lbs in 8 weeks and continues to do well 6 months after the procedure. Currently, there are no data to suggest optimal time for stent removal but there are anecdotal reports of gastroenterostomy tract closure after LAMS removal.

Safety and Efficacy of EUS-GE

Since this is a new technique, the data evaluating its efficacy and safety is limited to a few small studies. The data includes patients with benign and malignant gastric outlet obstruction and reported the results of ten patients,7 twenty patients6 and twenty-six patients,8 describing 90% technical success rates, and clinical success rates of 90%6,7 and 85%.8

By analyzing these studies, even though the number of patients is limited, the rate of adverse events was low (less than 5%). Nonetheless, it is important to note that when complications happen these are not trivial. Khashab et al.7 reported one case of stent misdeployment that ultimately resulted in conversion to a surgical gastrojejunostomy. The case series by Itoi et al.6 reported two stent misdeployements and the multicenter study published by Tyberg et al.8 reported one case of bleeding, one case of post procedural pain and one patient who developed peritonitis and died the following day after the procedure. Therefore, close collaboration with surgery and review of the technique is key to ensure success during this intervention.

CONCLUSION

EUS-guided gastroenterostomy (EUS-GE) is a novel, minimally invasive technique that can be used to palliate the symptoms of gastroduodenal outlet obstruction due to benign or malignant conditions. Due to the risk for serious adverse events, no current standardized technique and limited published data, this endoscopic technique should only be undertaken by experienced endosonographers. Furthermore, use of CE-LAMS for EUS-GE is not currently an FDA approved indication. Multidisciplinary care is strongly encouraged, incorporating surgeons, radiologists and gastroenterologists to ensure proper patient selection. EUS-GE remains to be prospectively evaluated, but early results show promise in the treatment of gastric outlet obstruction. This technique may be of particular interest for benign indications where long-term stent patency is desired but more study is warranted.

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