Camilleri, Michael

Abstract Purpose Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements. Methods Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7–36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and hip circumference. Results Thirty-five participants (17 liraglutide; 18 placebo) completed the trial. Compared to placebo group, liraglutide group had significant reductions in MTV; prospective food consumption score; desire to eat something sweet, salty, savory or fatty; and an increase in perceived fullness. Postprandial plasma levels of GLP-1 decreased and PYY levels increased with liraglutide relative to baseline. Significant reductions in total body, trunk, and upper and lower body fat without reduction in lean body mass were observed. Conclusion Liraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass.

AbstractBackgroundThe relationship between cardiovascular and gastrointestinal (ie, plasma pancreatic polypeptide [PP] response to modified sham feeding [MSF]) indices of vagal function is unclear. Hyperglycemia inhibits PP secretion via vagally mediated mechanisms. Our aims were to (a) compare the PP response, (b) its relationship with glycemia, and (c) the relationship between PP response to MSF, gastric emptying (GE) of solids, and symptoms during GE study in healthy controls, patients with diabetic gastroenteropathy (DM), and non‐ulcer dyspepsia (NUD).MethodsIn 24 healthy controls, 40 DM, and 40 NUD patients, we measured plasma PP concentrations during MSF, cardiovagal functions, GE, and symptoms during a GE study.Key ResultsBaseline PP concentrations were higher in DM than in controls and NUD (P = .01), and in type 2 than in type 1 DM patients (P < .01). The PP increment during MSF was normal (≥20 pg/mL) in 70% of controls, 54% of DM, and 47% of NUD patients. Overall, the PP response and cardiovagal tests were concordant (P = .01). Among patients with a reduced PP increment with MSF, 7/10 of T1DM and 1/7 of T2DM patients had moderate or severe cardiovagal dysfunctions (P < .05). The PP response to MSF was not associated with GE.Conclusions & InferencesUp to 30% of healthy controls have a reduced PP increment during MSF, limiting the utility of this test to detect vagal injury. The PP response is more useful when it is normal than abnormal. A reduced PP response is more likely to be associated with cardiovagal dysfunctions in T1DM than in T2DM.

AbstractThe objective of this mini‐review is to provide insights on the advances in the understanding of the genetic variants associated with different manifestations of Hirschsprung disease, which may present with a range of denervation from a short segment of colon to total colonic and small bowel or extensive aganglionosis. A recent article in this journal documented potential gene variants involved in long‐segment Hirschsprung disease in 23 patients. Gene variants were identified using a 31‐gene panel of genes related to Hirschsprung disease or enteric neural crest cell development, as previously reported in the literature. The study identified potentially harmful variants in eight genes across 13 patients, with a detection rate of 56.5% (13/23 patients). Five patients had pathologic variants in RET, NRG1, and L1CAM, and the remainder were considered variants of unknown significance. The authors attempted prenatal diagnosis of Hirschsprung disease utilizing an amniocentesis sample obtained for advanced maternal age in a family with a known deleterious RET mutation, manifested in the father (long‐segment Hirschsprung disease) and older daughter (total colonic aganglionosis). The fetus had the same RET variant but, after several years of follow‐up, has not developed any symptoms of Hirschsprung disease, supporting the conclusion that this RET mutation is an autosomal dominant gene with incomplete penetrance. This experience suggests that genetic counseling is appropriate to carefully assess the justification of prenatal testing, especially, when the phenotype of long‐segment Hirschsprung disease is so variable and the disease is potentially curable with surgery.

INTRODUCTION: Gastric food residue (GFR) identified during gastrointestinal (GI) endoscopy is assumed to reflect delayed gastric emptying (GE [i.e., gastroparesis]). The aims of this study aims were to determine i) the prevalence of GFR during upper GI endoscopy (EGD) and, ii) the relationship between GFR and GE, structural abnormalities and diseases associated with gastroparesis. METHODS: Electronic health records were used to identify patients who had undergone both EGD and gastric emptying scintigraphy (GES) between October 2013 and September 2018. The test meal included radiolabeled scrambled eggs (320 kcal, 30% fat). Data were collected via the Advanced Cohort Explorer (ACE) application available at Mayo Clinic. The presence of GFR, structural or physiological factors associated with delayed GE was determined. Descriptive and comparative analyses were performed. RESULTS: In the 5 year period, the prevalence of GFR during upper GI endoscopy was 3.2% per patient and 2.5% per procedure (37% or patients had undergone >1 procedure). Of 3169 patients who underwent both EGD and GES available for review, 230 (7.3%) had GFR. Type 1 diabetes mellitus (DM, 22% vs 7%, P < 0.001) and type 2 DM (13% vs 7%, P < 0.05), but not systemic sclerosis ( P = 0.1), were associated with GFR. Relative to patients with no GFR, patients with GFR had reduced GE at 2 and 4 hours (35% vs 46%, P < 0.001 and 67% vs 81%, P < 0.001 respectively) and were more likely to have structural abnormalities in the stomach or small bowel (e.g., surgery/stenosis, 14% GFR vs. 5%, P < 0.001) or have predisposing medical conditions (e.g. DM, systemic sclerosis, 20% GFR vs. 8%, P < 0.001). GE rates for patients with these conditions are shown in Table 1. Among those with no structural abnormalities or medical conditions associated with delayed GE, GE at 2 hours and 4 hours was significantly reduced in patient with GFR compared to those without GFR (37% vs 46%, and 69% vs 81%, both P < 0.001 respectively). The proportion of patients with delayed GE at 2 and 4 hours was greater in patients with GFR than without (42% vs 22% and 35% vs. 54%, both P < 0.001). CONCLUSION: GFR is encountered in 3% of all EGDs. In a cohort undergoing endoscopy and GES, ∼20% of patients with type 1 DM demonstrated GFR. The presence of GFR during endoscopy is associated with retarded GE. However, almost 50% of patients with GFR will have normal GE; therefore the presence of GFR at EGD does not accurately reflect gastric retention of digestible solids.

INTRODUCTION: Reduced gastric accommodation (GA) or accelerated or delayed gastric emptying (GE) contributes to pathophysiology in functional dyspepsia (FD). Secretin is an endogenous hormone secreted postprandially from the duodenal mucosa. Our objective was to determine the effects of secretin in human gastric motor functions and satiation in health and FD. METHODS: We conducted a double-blind, randomized, placebo-controlled, cross-over trial in 10 healthy participants and 10 patients with FD by Rome IV criteria. Subjects were randomized to IV secretin or normal saline with a 1-4 week washout period. We measured GA using validated 99m Tc-single photon emission computed tomography with a standardized 300 mL meal of 111 In radiolabeled Ensure®. We measured GE using scintigraphy of the same meal and symptoms 30 minutes post meal based on 100 mm visualized analog scale (VAS). To measure volume to fullness (VTF) and maximum tolerated volume (MTV), we performed Ensure® nutrient drink test (NDT) and recorded symptoms 30 min post-MTV. Wilcoxon Signed-Rank Test was used for comparison within healthy and FD groups and ANCOVA modeling was used for intention to treat comparison between groups, adjusting for age, sex, and treatment arm (secretin vs. placebo). Study drug was provided by ChiroClin, Inc. RESULTS: The median age for healthy volunteers (HV) was 45.0 years [IQR: 38.0, 49.0 (80% female)] and for FD was 50.5 years [42.0, 55.0 (70% female)]. There was no statistical difference in either group for secretin vs. placebo for GA. Secretin delayed GE in both HV and FD (Table 1). There was decrease in GE for secretin vs. placebo in HV at 20 minutes [-10% (-13, -7), P = 0.008] and 30 minutes [-11% (-16, -4), P = 0.004]. This finding was also seen in the FD group for GE at 25 minutes [-5% (-9, 0), P = 0.047] and 30 minutes [-8% (-9, 0), P = 0.03]. There were no statistically significant differences between treatment arms for VTF or MTV in either HV or FD. On ANCOVA analysis, there were statistically significant increases in nausea at 30 minutes ( P = 0.0016) and fullness at 30 minutes ( P = 0.0002) for secretin vs. placebo in FD compared to HV. CONCLUSION: Secretin delayed GE in both healthy volunteers and FD without significantly altering GA, VTF, or MTV. Secretin receptor stimulation deserves further study in FD patients with accelerated GE.

INTRODUCTION: Increasing rates of obesity have led to increased numbers of bariatric surgeries performed world-wide. However, some patients do not achieve significant weight loss or develop weight regain following these procedures. Other than estimating the size of the gastric remnant at endoscopy or transaxial imaging, there are limited approaches to quantitate the function of the post-surgical stomach in order to evaluate the disparate weight patterns, or to develop strategy for future treatments, e.g., pharmacotherapy or endoscopic intervention. We hypothesize that altered gastric function in the pre- and post-surgical periods may offer an explanation. Studies performed thus far are difficult to interpret due to heterogeneity in approaches to diagnostic evaluation. The aims of this project were: to assess the feasibility of a new protocol for simultaneous evaluation of gastric accommodation and gastric emptying in the post-bariatric state; and to report normative values in healthy volunteers. METHODS: Methods: We utilized single photon emission computed tomography (SPECT) and gamma scintigraphy to concurrently study postprandial gastric accommodation responses and gastric emptying rates of a limited size meal designed for subsequent use in post-bariatric patients. The standard meal consisted of 1 egg and 1 extra egg yolk scrambled with 111 Indium-activated charcoal (∼130kcal, 9.5g fat) and 120mL 2% milk (130kcal, 4.4g fat). Gastric accommodation was measured using 99m Technetium-SPECT. SPECT imaging was obtained concomitant with gastric emptying of the 111 In-labeled meal. Anterior and posterior scans of the abdomen were obtained for estimating gastric emptying parameters every 15 minute until 90 minutes, and then in 30-minute intervals until 240 minutes or complete emptying. RESULTS: Data on 28/30 healthy volunteers (35.7% men; 67% Caucasian) with completed studies to date are shown in the Table 1 (data presented as mean ± standard deviation). Gastric emptying proportion at 1, 2, and 4 hours, T 1/2 , and gastric volumes including accommodation are graphically depicted in Figures 1 and 2, respectively. CONCLUSION: Discussion: This study has demonstrated feasibility of simultaneous measurement of gastric emptying and accommodation and provides normal values; this sets the stage for future baseline and post-operative scans on patients undergoing sleeve gastrectomy.

INTRODUCTION: Patients with inflammatory bowel disease (IBD), whether Crohn's disease (CD) or ulcerative colitis (UC), have known alterations in the enterohepatic circulation of bile acids (BA) that may contribute to chronic diarrhea, but the fecal BA patterns are not well defined. We aimed to audit all patients with IBD who had fecal BA measurements as part of evaluation of chronic diarrhea at a tertiary care center. METHODS: Methods: 65 patients with IBD (18 with UC and 47 with CD) were evaluated at a single center and underwent measurements of fecal total and individual BAs based on a 48-hour collection performed at the end of a 4-day, 100-gram fat diet. The electronic medical records were interrogated to obtain type of IBD, disease activity, location of disease, prior surgery, IBD related therapies, presenting symptoms, and response to treatment with BA sequestrants. Bile acid diarrhea (BAD) diagnosis was based on >10% primary BAs, >4% primary BAs + >1,000 µmol/48 h, or total fecal BAs >2,337 µmol/48 h. IBD disease activity was based on radiologic, endoscopic and histologic parameters. Data are reported as mean ± standard error of the mean (SEM). RESULTS: Table 1 summarizes the patterns of BAD in our cohort with IBD. Figure 1 demonstrates the mean ± SEM of total fecal BAs and % primary BAs in each group of IBD patients. Among patients with UC, 10 had poorly controlled disease and 8 had well controlled disease, and both cohorts had elevated primary BAs (mean 28.9% ± 12.5%; 34.6% ± 21%, respectively). All patients with an ileal pouch anal anastomosis (IPAA) had elevated total fecal BAs (BADt) compared to those with an intact colon. In patients with CD, those with ileal resections had elevated BADt and % primary BAs (6263 µmol/48 h ± 1012 µmol/48 h; 79% ± 5.9%, respectively). Patients with an intact ileum, had elevated % primary BAs regardless of disease activity: controlled CD 34.7% ± 9.3%; poorly controlled CD 57.8% ± 9.5%; 15 out of 47 patients with CD were started on BA sequestrants with a positive response in 10/15. CONCLUSION: Discussion: BAs may play a role in the pathophysiology of chronic diarrhea in patients with IBD, regardless of inflammatory disease activity. Future studies are required to assess the impact of fecal bile acid testing and treatment with BA sequestrants on inflammation and chronic diarrhea in patients with IBD.

INTRODUCTION: Loey Dietz syndrome (LDS) is an autosomal dominant disorder caused by a mutation in TGFBR1 - or TGFBR2. LDS is characterized by distinctive facies, tortuous arteries and aortic aneurysms predisposition to eosinophilic allergic disorders including eosinophilic esophagitis and gastritis, and other systemic findings including inflammatory bowel disease. Patients with vascular Ehlers Danlos Syndrome (vEDS) have deficiency in type III collagen and have similar vascular laxity and concomitant GI manifestations. This connective tissue vulnerability contributes to increased post-operative wound dehiscence and development of hernias. Our aim was to summarize abdominal wall and GI tract manifestations in these two rare vascular disorders at a tertiary referral center. METHODS: Data were collected via Advanced Cohort Explorer (ACE) application at Mayo Clinic. A chart review was undertaken on patients with a confirmed diagnosis of vEDS or LDS seen at Mayo Clinic in Rochester from 1994 to 2018. Diagnoses were confirmed by genetic testing and/or clinical review through the specialized medical genetics clinic. Information was extracted on vascular complications of disease, prevalence of abdominal hernias, and gastrointestinal symptoms. The study was reviewed and exempted by the Mayo Clinic IRB. RESULTS: We identified and reviewed records of 50 vEDS and 13 LDS patients; data are summarized in Tables 1 and 2. Patients were similar in age at diagnosis and gender distribution. Hernias were present in similar proportions of patients with vEDS and LDS, although ventral hernias were more frequent and the hernias were more likely to be post-operative in vEDS than in LDS. LDS patients had more aneurysms (58% vEDS vs. 76.9% LDS, P = 0.02) with higher proportion requiring arterial repair (32.7% vEDS vs. 69.2% LDS, P = 0.03). Co-morbidities more prevalent in LDS than vEDS were autonomic dysfunction, psychopathology and allergy. We did not note increase in symptoms suggestive of eosinophilic esophagitis/gastritis in the LDS patients. GI symptoms were prevalent in both disorders and largely similar, except for diarrhea and constipation which were both significantly more prevalent in LDS patients. CONCLUSION/DISCUSSION: While vEDS and LDS are both connective tissue disorders with propensity for GI symptoms, abdominal hernias and aneurysm formation, the risk of arterial rupture and co-morbidity of autonomic dysfunction, psychopathology and allergy are greater in LDS than vEDS.

INTRODUCTION: There is still controversy surrounding the use of symptoms, history, and tests for diagnosis of rectal evacuation disorders (RED) and slow transit constipation (STC). We performed a comprehensive literature-based analysis to ascertain pooled prevalence, sensitivity (SN), specificity (SP), and likelihood ratios (LR) for clinical parameters to determine pre- and post-test probabilities of diagnosing RED and STC without RED. METHODS: Using MEDLINE and PUBMED, we examined systematic and clinical reviews, meta-analyses, primers, guidelines, and consensus statements since 1999 to determine the diagnostic utility of history, symptoms, and testing for RED and STC. Studies were included if binary data were available to assess true/false positives or negatives to pool and calculate SN/SP/LR. Given there are no “gold standard” diagnostic criteria for RED or STC, designation of “true” RED or STC was based on confirmation by at least one objective anorectal or colonic transit test. Controls varied across studies; all had normal anorectal and/or transit tests by the specific protocol used in each study. We assessed STC alone (associated with normal anorectal testing). RESULTS: We reviewed 97 articles involving studies from many different countries, and 63 articles for RED and 61 articles for STC met inclusion/exclusion criteria. The prevalence of disease phenotypes among 4160 patients with chronic constipation based on objective testing was RED alone 23.3%, normal transit constipation (NTC) alone 31.9%, STC alone 16.2%, and RED + STC 14.3%. To diagnose RED (Figure 1, Table 1), the most clinically significant symptoms included hard/lumpy stools (+LR 269.6, n = 1583) and urinary symptoms (100% specificity, n = 58). The strongest digital rectal exam (DRE) findings were poor anal relaxation (+LR 5.3, n = 529) or increased anal squeeze (+LR 8.4, n = 395). The most predictive anorectal tests were balloon expulsion time >120 s (+LR 5.5, n = 551) and rectoanal pressure gradient < −40 mmHg with high anal pressure on straining on anorectal manometry (100% specificity, n = 101). For STC alone, the most predictive symptom was a call to stool (+LR 10.5, n = 75). Patients without abdominal distension/fullness/bloating were less likely to have RED (−LR 0.2, n = 324) or STC alone (−LR 0.2, n = 93). CONCLUSION: Symptom assessments and DREs are critical in the evaluation for RED and STC. RED is highly prevalent in patients presenting with chronic idiopathic constipation.