Efficacy and safety of apraglutide in short bowel syndrome with intestinal failure and colon-in-continuity: A multicenter, open-label, metabolic balance study.

BACKGROUND: Apraglutide is a novel long-acting GLP-2 analog in development for short bowel syndrome with intestinal failure (SBS-IF). This multicenter, open-label, phase 2 study in SBS-IF and colon-in-continuity (CiC) investigates the safety and efficacy of apraglutide. METHODS: This was a 52-week phase 2 metabolic balance study (MBS) in 9 adult patients with SBS-IF-CiC receiving once-weekly subcutaneous apraglutide injections. Safety was the primary endpoint. Secondary endpoints included changes in absorption parameters (MBS at baseline, after 4 weeks with stable parenteral support (PS), and 48 weeks), PS needs (48-week PS adjustment period based on monthly 48-h fluid balances) and intestinal morphology and motility (static and cine MRI at baseline and 4, 24 and 48 weeks). RESULTS: PS volume decreased by -4702 mL/week (-52 %; p < 0.001) at week 52. Seven patients (78 %) achieved ≥1 day off PS at week 52. At 4 weeks, fecal output was reduced by 253 g/day (p = 0.013). At 48 weeks, increases in wet weight absorption by 316 g/day (p = 0.039), energy absorption by 1134 kJ/day (p = 0.041) and carbohydrate absorption by 56.1 g/day (p = 0.024) were observed. Moreover, small bowel length increased from 29.7 to 40.7 cm (p = 0.012), duodenal wall thickness increased by 0.8 mm (p = 0.02) and motility in the proximal colon was reduced (p = 0.031). A total of 127 adverse events was reported, which were mostly mild to moderate. CONCLUSION: Apraglutide had an acceptable safety profile and was associated with significant reductions in PS needs and days off PS, improvements in intestinal absorption, and structural and functional intestinal changes in patients with SBS-IF-CiC. CLINICALTRIALS: gov, Number NCT04964986.

Combined MRI, high-resolution manometry and a randomised trial of bisacodyl versus hyoscine show the significance of an enlarged colon in constipation: the RECLAIM study.

BACKGROUND: Colonic motility in constipation can be assessed non-invasively using MRI. OBJECTIVE: To compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response. DESIGN: Part 1: 44 healthy volunteers (HVs), 43 patients with irritable bowel syndrome with constipation (IBS-C) and 37 with functional constipation (FC) completed stool diaries and questionnaires and underwent oral macrogol (500-1000 mL) challenge. Whole gut transit time (WGTT), segmental colonic volumes (CV), MRI-derived Motility Index and chyme movement by 'tagging' were assessed using MRI and time to defecation after macrogol recorded. Left colonic HRCM was recorded before and after a 700 kcal meal. Patients then proceeded to Part 2: a randomised cross-over study of 10-days bisacodyl 10 mg daily versus hyoscine 20 mg three times per day, assessing daily pain and constipation. RESULTS: Part 1: Total CVs median (range) were significantly greater in IBS-C (776 (595-1033)) and FC (802 (633-951)) vs HV (645 (467-780)), p<0.001. Patients also had longer WGTT and delayed evacuation after macrogol. IBS-C patients showed significantly reduced tagging index and less propagated pressure wave (PPW) activity during HRCM versus HV. Compared with FC, IBS-C patients were more anxious and reported more pain. Abnormally large colons predicted significantly delayed evacuation after macrogol challenge (p<0.02), impaired manometric meal response and reduced pain with bisacodyl (p<0.05).Part 2: Bisacodyl compared with hyoscine increased bowel movements but caused more pain in both groups (p<0.03). CONCLUSION: An abnormally large colon is an important feature in constipation which predicts impaired manometric response to feeding and treatment responses. HRCM shows that IBS-C patients have reduced PPW activity. TRIAL REGISTRATION NUMBER: The study was preregistered on ClinicalTrials.gov, Reference: NCT03226145.

Volumetric measurement of terminal ileal Crohn's disease by magnetic resonance enterography: a feasibility study.

OBJECTIVES: Magnetic resonance enterography (MRE) interpretation of Crohn's disease (CD) is subjective and uses 2D analysis. We evaluated the feasibility of volumetric measurement of terminal ileal CD on MRE compared to endoscopy and sMARIA, and the responsiveness of volumetric changes to biologics. METHODS: CD patients with MRE and contemporaneous CD endoscopic index of severity-scored ileocolonoscopy were included. A centreline was placed through the terminal ileum (TI) lumen defining the diseased bowel length on the T2-weighted non-fat saturated sequence, used by two radiologists to independently segment the bowel wall to measure volume (phase 1). In phase 2, we measured disease volume in patients treated with biologics, who had undergone pre- and post-treatment MRE, with treatment response classified via global physician assessment. RESULTS: Phase 1 comprised 30 patients (median age 29 (IQR 24, 34) years). Phase 2 included 12 patients (25 years (22, 38)). In phase 1, the mean of the radiologist-measured volumes was used for analysis. The median disease volume in those with endoscopically active CD was 20.9 cm3 (IQR 11.3, 44.0) compared to 5.7 cm3 (2.9, 9.8) with normal endoscopy. The mean difference in disease volume between the radiologists was 3.0 cm3 (limits of agreement -21.8, 15.9). The median disease volume of patients with active CD by sMARIA was 15.0 cm3 (8.7, 44.0) compared to 2.85 cm3 (2.6, 3.1) for those with inactive CD. Pre- and post-treatment median disease volumes were 28.5 cm3 (26.4, 31.2), 11 cm3 (4.8, 16.6), respectively in biological responders, vs 26.8 cm3 (12.3, 48.7), 40.1 cm3 (10, 56.7) in non-responders. CONCLUSION: Volumetric measurement of terminal ileal CD by MRE is feasible, related to endoscopy and sMARIA activity, and responsive to biologics. CLINICAL RELEVANCE STATEMENT: Measuring the whole volume of diseased bowel on MRE in CD is feasible, related to how biologically active the disease is when assessed by endoscopy and by existing MRE activity scores, and is sensitive to treatment response. KEY POINTS: MRE reporting for CD is subjective and uses 2D images rather than assessing the full disease volume. Volumetric measurement of CD relates to endoscopic activity and shows reduced disease volumes in treatment responders. This technique is an objective biomarker that can assess disease activity and treatment response, warranting validation.

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study.

Background: People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods: We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results: We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions: Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrialsgov registration: NCT04006873 (02/07/2019).

Impact of bowel dilation on small bowel motility measurements with cine-MRI: assessment of two quantification techniques.

Objectives: To evaluate the effect of bowel dilation on cine-MRI small bowel motility measurements, by comparing a conventional motility score (including bowel wall and lumen) with a bowel wall-specific motility score in healthy and diseased populations. Methods: Four populations were included: 10 Crohn's patients with a stricture and prestricture dilation for segmental motility analysis, and 14 mannitol-prepared healthy subjects, 15 fasted healthy subjects and eight chronic intestinal pseudo-obstruction (CIPO) patients (characterized by dilated bowel loops) for global small bowel motility analysis. All subjects underwent a cine-MRI scan from which two motility scores were calculated: a conventional score (including bowel wall and lumen) and a bowel wall-specific score. The difference between the two scores was calculated per population and compared between groups with a one-way ANOVA and Tukey-Kramer analysis. Results: In Crohn's patients, the median (IQR) change between the conventional and wall-specific motility score was 0% (-2 to +4%) within the stricture and 0% (-1 to +7%) in the prestricture dilation. For the global small bowel, this was -1% (-5 to 0%) in mannitol-prepared healthy subjects, -2% (-6 to +2%) in fasted healthy subjects and +14% (+6 to+20%) in CIPO patients. The difference between the two motility scores in CIPO patients differed significantly from the four other groups (p = 0.002 to p < 0.001). Conclusions: The conventional small bowel motility score seems robust in Crohn's disease patients and healthy subjects. In patients with globally and grossly dilated bowel loops, a bowel-wall specific motility score may give a better representation of small bowel motility. Advances in knowledge: These findings support researchers and clinicians with making informed choices for using cine-MRI motility analysis in different populations.

Magnetic resonance imaging assessed enteric motility and luminal content analysis in patients with severe bloating and visible distension.

BACKGROUND: Gastrointestinal symptoms in functional gut disorders occur without any discernible structural gut abnormality. Preliminary observations on enteric MRI suggest possible abnormal content and motility of the terminal ileum (TI) in constipation-predominant IBS (IBS-C) with severe bloating, and in functional bloating and distension (FABD) patients. We investigated whether MRI can quantify differences in small bowel (SB) content and motility between patients and healthy controls (HCs). METHODS: 11 IBS-C (mean age 40 [21-52] years; 10 women) and 7 FABD (36 [21-56]; all women) patients with bloating and 20 HCs (28 [22-48]; 6 women) underwent enteric MRI, including dynamic motility and anatomical sequences. Three texture analysis (TA) parameters assessed the homogeneity of the luminal content, with ratios calculated between the TI and (1) the SB and (2) the ascending colon. Four TI motility metrics were derived. Ascending colon diameter (ACD) was measured. A comparison between HCs and patients was performed independently for: (1) three TA parameters, (2) four TI motility metrics, and (3) ACD. KEY RESULTS: Compared with HCs, patients had TI:colon ratios higher for TA contrast (p < 0.001), decreased TI motility (lower mean motility [p = 0.04], spatial motility variation [p = 0.03], and area of motile TI [p = 0.03]), and increased ACD (p = 0.001). CONCLUSIONS AND INFERENCES: IBS-C and FABD patients show reduced TI motility and differences in luminal content compared with HCs. This potentially indicates reflux of colonic contents or delayed clearance of the TI, which alongside increased ACD may contribute to symptoms of constipation and bloating.

Magnetic resonance imaging of the gastrointestinal tract shows reduced small bowel motility and altered chyme in cystic fibrosis compared to controls.

People with cystic fibrosis (CF) experience digestive symptoms but the mechanisms are incompletely understood. Here we explore causes and consequences of slower gastrointestinal transit using magnetic resonance imaging (MRI). Twelve people with CF and 12 healthy controls, matched for age and gender, underwent MRI scans, both fasted and after standardised meals, over 6.5 h. Fasted small bowel motility scores were lower in CF than in controls. No difference in ascending colon chyme T1 was detected. The difference in texture between small bowel and colon contents, seen in health, was diminished in CF. The ascending colon in CF participants had an abnormal appearance compared to controls. MRI offers unique potential to evaluate gut luminal content, colonic mucosa and intestinal motor activity. These new data support the theoretical cycle of desiccation, dysmotility and delayed transit as a cause of gastrointestinal symptoms in CF.

Cardiac-induced liver deformation as a measure of liver stiffness using dynamic imaging without magnetization tagging-preclinical proof-of-concept, clinical translation, reproducibility and feasibility in patients with cirrhosis.

PURPOSE: MR elastography and magnetization-tagging use liver stiffness (LS) measurements to diagnose fibrosis but require physical drivers, specialist sequences and post-processing. Here we evaluate non-rigid registration of dynamic two-dimensional cine MRI images to measure cardiac-induced liver deformation (LD) as a measure of LS by (i) assessing preclinical proof-of-concept, (ii) clinical reproducibility and inter-reader variability, (iii) the effects of hepatic hemodynamic changes and (iv) feasibility in patients with cirrhosis. METHODS: Sprague-Dawley rats (n = 21 bile duct ligated (BDL), n = 17 sham-operated controls) and fasted patients with liver cirrhosis (n = 11) and healthy volunteers (HVs, n = 10) underwent spoiled gradient-echo short-axis cardiac cine MRI studies at 9.4 T (rodents) and 3.0 T (humans). LD measurements were obtained from intrahepatic sub-cardiac regions-of-interest close to the diaphragmatic margin. One-week reproducibility and prandial stress induced hemodynamic changes were assessed in healthy volunteers. RESULTS: Normalized LD was higher in BDL (1.304 ± 0.062) compared with sham-operated rats (1.058 ± 0.045, P = 0.0031). HV seven-day reproducibility Bland-Altman (BA) limits-of-agreement (LoAs) were ± 0.028 a.u. and inter-reader variability BA LoAs were ± 0.030 a.u. Post-prandial LD increases were non-significant (+ 0.0083 ± 0.0076 a.u., P = 0.3028) and uncorrelated with PV flow changes (r = 0.42, p = 0.2219). LD measurements successfully obtained from all patients were not significantly higher in cirrhotics (0.102 ± 0.0099 a.u.) compared with HVs (0.080 ± 0.0063 a.u., P = 0.0847). CONCLUSION: Cardiac-induced LD is a conceptually reasonable approach from preclinical studies, measurements demonstrate good reproducibility and inter-reader variability, are less likely to be affected by hepatic hemodynamic changes and are feasible in patients with cirrhosis.

Emerging Imaging Biomarkers in Crohn Disease.

ABSTRACT: In this review article, we present the latest developments in quantitative imaging biomarkers based on magnetic resonance imaging (MRI), applied to the diagnosis, assessment of response to therapy, and assessment of prognosis of Crohn disease. We also discuss the biomarkers' limitations and future prospects. We performed a literature search of clinical and translational research in Crohn disease using diffusion-weighted MRI (DWI-MRI), dynamic contrast-enhanced MRI (DCE-MRI), motility MRI, and magnetization transfer MRI, as well as emerging topics such as T1 mapping, radiomics, and artificial intelligence. These techniques are integrated in and combined with qualitative image assessment of magnetic resonance enterography (MRE) examinations. Quantitative MRI biomarkers add value to MRE qualitative assessment, achieving substantial diagnostic performance (area under receiver-operating curve = 0.8-0.95). The studies reviewed show that the combination of multiple MRI sequences in a multiparametric quantitative fashion provides rich information that may help for better diagnosis, assessment of severity, prognostication, and assessment of response to biological treatment. However, the addition of quantitative sequences to MRE examinations has potential drawbacks, including increased scan time and the need for further validation before being used in therapeutic drug trials as well as the clinic.

Quantitative assessment of terminal ileum motility on MR enterography in Crohn disease: a feasibility study in children.

OBJECTIVES: Investigate the relationship between quantified terminal ileal (TI) motility and histopathological activity grading, Crohn Disease MRI Index (CDMI) and faecal calprotectin. METHODS: Retrospective review of children with Crohn disease or unclassified inflammatory bowel disease, who underwent MR enterography. Dynamic imaging for 25 patients (median age 12, range 5 to 16) was analysed with a validated motility algorithm. The TI motility score was derived. The primary reference standard was TI Endoscopic biopsy Assessment of Inflammatory Activity (eAIS) within 40 days of the MR enterography. Secondary reference standards: (1) the Crohn Disease MRI Index (CDMI) and (2) faecal calprotectin levels. RESULTS: MR enterography median motility score was 0.17 a.u. (IQR 0.12 to 0.25; range 0.05 to 0.55), and median CDMI was 3 (IQR 0 to 5.5). Forty-three percent of patients had active disease (eAIS > 0) with a median eAIS score of 0 (IQR 0 to 2; range 0 to 5). The correlation between eAIS and motility was r = - 0.58 (p = 0.004, N = 23). Between CDMI and motility, r = - 0.42 (p = 0.037, N = 25). Motility score was lower in active disease (median 0.12 vs 0.21, p = 0.020) while CDMI was higher (median 5 vs 1, p = 0.04). In a subset of 12 patients with faecal calprotectin within 3 months of MR enterography, correlation with motility was r = - 0.27 (p = 0.4). CONCLUSIONS: Quantified terminal ileum motility decreases with increasing histopathological abnormality in children with Crohn disease, reproducing findings in adults. TI motility showed a negative correlation with an MRI activity score but not with faecal calprotectin levels. KEY POINTS: • It is feasible to perform MRI quantified bowel motility assessment in children using free-breathing techniques. • Bowel motility in children with Crohn disease decreases as the extent of intestinal inflammation increases. • Quantified intestinal motility may be a candidate biomarker for treatment efficacy in children with Crohn disease.

MR Measures of Small Bowel Wall T2 Are Associated With Increased Permeability.

BACKGROUND: Increased small bowel permeability leads to bacterial translocation, associated with significant morbidity and mortality. Biomarkers are needed to evaluate these changes in vivo, stratify an individual's risk, and evaluate the efficacy of interventions. MRI is an established biomarker of small bowel inflammation. PURPOSE: To characterize changes in the small bowel with quantitative MRI measures associated with increased permeability induced by indomethacin. STUDY TYPE: Prospective single-center, double-blind, two-way crossover provocation study. SUBJECTS: A provocation cohort (22 healthy volunteers) and intrasubject reproducibility cohort (8 healthy volunteers). FIELD STRENGTH/SEQUENCE: 2D balanced turbo field echo sequences to measure small bowel wall thickness, T2 , and motility acquired at 3T. ASSESSMENT: Participants were randomized to receive indomethacin or placebo prior to assessment. After a minimum 2-week washout, measures were repeated with the alternative allocation. MR measures (wall thickness, T2 , motility) at each study visit were compared to the reference standard 2-hour lactulose/mannitol urinary excretion ratio (LMR) test performed by a lab technician. All analyses were performed blind. STATISTICAL TESTS: Normality was tested (Shapiro-Wilk's test). Paired testing (Student's t-test or Wilcoxon) determined the significance of paired differences with indomethacin provocation. Pearson's correlation coefficient compared significant measures with indomethacin provocation to LMR. Intrasubject (intraclass correlation) and interrater variability (Bland-Altman) were assessed. RESULTS: Indomethacin provocation induced a significant increase in LMR compared to placebo (P < 0.05) and a significant increase in small bowel T2 (0.12 seconds compared to placebo 0.07 seconds, P < 0.05). Small bowel wall thickness (P = 0.17) and motility (P = 0.149) showed no significant change. T2 and LMR were positively correlated (r = 0.68, P < 0.05). T2 measurements were robust to interobserver (intraclass correlation 0.89) and intrasubject variability (Bland-Altman bias of 0.005 seconds, 95% confidence interval [CI] -0.04 to +0.05 seconds, and 0.0006 seconds, 95% CI -0.05 to +0.06 seconds). DATA CONCLUSION: MR measures of small bowel wall T2 were significantly increased following indomethacin provocation and correlated with 2-hour LMR test results. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Measurement of fasted state gastric antral motility before and after a standard bioavailability and bioequivalence 240 mL drink of water: Validation of MRI method against concomitant perfused manometry in healthy participants.

OBJECTIVE: The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method. MATERIAL AND METHODS: Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later. RESULTS: Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence. CONCLUSION: Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes. CLINICAL TRIAL: This trial was registered at ClinicalTrials.gov as NCT03191045.

The MRI colonic function test: Reproducibility of the Macrogol stimulus challenge.

BACKGROUND: Magnetic resonance imaging (MRI) of the colonic response to a macrogol challenge drink can be used to assess the mechanisms underlying severe constipation. We measured the intrasubject reproducibility of MRI measures of colonic function to aid their implementation as a possible clinical test. METHODS: Healthy participants attended for MRI on two occasions (identical protocols, minimum 1 week apart). They underwent a fasted scan and then consumed the macrogol drink. Subjects were scanned at 60 and 120 minutes, with maximum value reached used for comparison. The colonic volume, water content, mixing of colonic content and the movement of the colon walls were measured. Coefficients of variation and intraclass correlation coefficients (ICC) were calculated. RESULTS: Twelve participants completed the study: nine female, mean age 26 years (SD 5) and body mass index 24.8 kg/m2 (SD 3.2). All measures consistently increased above baseline following provocation with macrogol. The volume, water content and content mixing had good intrasubject reproducibility (ICC volume = 0.84, water content = 0.93, mixing = 0.79, P < .001). With the wall movement, the response to the challenge was generally large, but more variable between visits resulting in a lower ICC overall (ascending colon = 0.65, descending colon = 0.76, P < .001). CONCLUSIONS: The colonic response to the macrogol stimulus as assessed by MRI is heterogeneous but large compared to baseline, with moderate to good reproducibility, making the test suitable to study potential pathologies underlying GI disorders such as constipation. More data are needed to better define the normal range for comparison with patient groups who may have both hypo- and hypermotile responses.

Serum Scoring and Quantitative Magnetic Resonance Imaging in Intestinal Failure-Associated Liver Disease: A Feasibility Study.

(1) Background: Intestinal failure-associated liver disease (IFALD) in adults is characterized by steatosis with variable progression to fibrosis/cirrhosis. Reference standard liver biopsy is not feasible for all patients, but non-invasive serological and quantitative MRI markers for diagnosis/monitoring have not been previously validated. Here, we examine the potential of serum scores and feasibility of quantitative MRI used in non-IFALD liver diseases for the diagnosis of IFALD steatosis; (2) Methods: Clinical and biochemical parameters were used to calculate serum scores in patients on home parenteral nutrition (HPN) with/without IFALD steatosis. A sub-group underwent multiparameter quantitative MRI measurements of liver fat fraction, iron content, tissue T1, liver blood flow and small bowel motility; (3) Results: Compared to non-IFALD (n = 12), patients with IFALD steatosis (n = 8) demonstrated serum score elevations in Enhanced Liver Fibrosis (p = 0.032), Aspartate transaminase-to-Platelet Ratio Index (p < 0.001), Fibrosis-4 Index (p = 0.010), Forns Index (p = 0.001), Gamma-glutamyl transferase-to-Platelet Ratio Index (p = 0.002) and Fibrosis Index (p = 0.001). Quantitative MRI scanning was feasible in all 10 sub-group patients. Median liver fat fraction was higher in IFALD steatosis patients (10.9% vs 2.1%, p = 0.032); other parameter differences were non-significant; (4) Conclusion: Serum scores used for non-IFALD liver diseases may be useful in IFALD steatosis. Multiparameter MRI is feasible in patients on HPN.

Gastrointestinal peptides and small-bowel hypomotility are possible causes for fasting and postprandial symptoms in active Crohn's disease.

BACKGROUND: Crohn's disease (CD) patients suffer postprandial aversive symptoms, which can lead to anorexia and malnutrition. Changes in the regulation of gut hormones and gut dysmotility are believed to play a role. OBJECTIVES: This study aimed to investigate small-bowel motility and gut peptide responses to a standard test meal in CD by using MRI. METHODS: We studied 15 CD patients with active disease (age 36 ± 3 y; BMI 26 ± 1 kg/m 2) and 20 healthy volunteers (HVs; age 31 ± 3 years; BMI 24 ± 1 kg/m 2). They underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling following a 400-g soup meal (204 kcal). Small-bowel motility, other MRI parameters, and glucagon-like peptide-1 (GLP-1), polypeptide YY (PYY), and cholecystokinin peptides were measured. Data are presented as means ± SEMs. RESULTS: HVs had significantly higher fasting motility indexes [106 ± 13 arbitrary units (a.u.)], compared with CD participants (70 ± 8 a.u.; P ≤ 0.05). Postprandial small-bowel water content showed a significant time by group interaction (P < 0.05), with CD participants showing higher levels from 210 min postprandially. Fasting concentrations of GLP-1 and PYY were significantly greater in CD participants, compared with HVs [GLP-1, CD 50 ± 8 µg/mL versus HV 13 ± 3 µg/mL (P ≤ 0.0001); PYY, CD 236 ± 16 pg/mL versus HV 118 ± 12 pg/mL (P ≤ 0.0001)]. The meal challenge induced a significant postprandial increase in aversive symptom scores (fullness, distention, bloating, abdominal pain, and sickness) in CD participants compared with HVs (P ≤ 0.05). CONCLUSIONS: The decrease in fasting small-bowel motility noted in CD participants can be ascribed to the increased fasting gut peptides. A better understanding of the etiology of aversive symptoms in CD will facilitate identification of better therapeutic targets to improve nutritional status. This trial was registered at clinicaltrials.gov as NCT03052465.

Spatio-temporal motility MRI analysis of the stomach and colon.

BACKGROUND: MRI is increasingly used to objectively assess gastrointestinal motility. However, motility metrics often do not offer insights into the nature of contractile action. This study introduces a systematic method of making spatio-temporal measurements of contractions, based on changes in bowel lumen diameter. METHODS: Two heterogeneous cohorts of subjects were selected displaying gastric (n = 15) and colonic motility (n = 20) on which to test the spatio-temporal motility MRI (STMM) technique. STMM involved delineating the bowel lumen along with inner and outer bowel wall along a section of the gastrointestinal tract. A series of diameter measurements were made automatically across the central axis of the lumen. Measurements were automatically propagated through the time series using a previously validated algorithm. Contractions were quantitatively summarized with two methods measuring (a) normalized contraction plot (NCP) and (b) combined velocity distance (CVD) both of which can be visualized as spatio-temporal motility maps. Both metrics were correlated against subjective visual scoring systems. KEY RESULTS: Good correlation was seen between reader scores and both motility metrics (NCP, R = 0.85, P < 0.001, CVD, R = 0.93, R < 0.001) in the gastric data. Good correlation was also seen between the reader scores and the two metrics in the colonic data (NCP, R = 0.82, P < 0.001, CVD, R = 0.78, R < 0.001). CONCLUSIONS AND INFERENCES: Spatio-temporal motility MRI analysis of the stomach and colon correlates well with reader scores in a range of datasets and provides both a quantitative and qualitative means of assessing contractile activity in the gastrointestinal tract.

Cine MRI assessment of motility in the unprepared small bowel in the fasting and fed state: Beyond the breath-hold.

BACKGROUND: The symptoms of functional bowel disorders are common in postprandial but investigations are generally undertaken in the fasted state using invasive procedures. MRI provides a noninvasive tool to study the gastrointestinal tract in an unperturbed, fed state. The aim of this study was to develop a technique to assess small bowel motility from cine MRI data in the unprepared bowel in fasting and fed states. METHODS: Fifteen healthy volunteers underwent a baseline MRI scan after which they consumed a 400 g soup. Subjects then underwent a postprandial scan followed by further scans at regular intervals. Small bowel motility was assessed using single-slice bTFE cine MRI. An optimized processing technique was used to generate motility data based on power spectrum analysis of voxel-signal changes with time. Interobserver variability (n = 15) and intra-observer (n = 6) variability were assessed. Changes in the motility index were compared between fasted and immediate postprandial state. KEY RESULTS: Excellent agreement between observers was seen across the range of motility measurements acquired, with intraclass correlation coefficient (ICC) of 0.979 (P < 0.0001) and Bland-Altman limits of agreement 95% CI: -28.9 to 45.9 au. Intra-observer variability was low with ICC of 0.992 and 0.960 (2 observers, P < 0.0001). Changes from the fasted to immediately postprandial state showed an average increase of 122.4% ± 98.7% (n = 15). CONCLUSIONS & INFERENCES: This optimized technique showed excellent inter and intra observer agreement. It was sensitive to changes in motility induced feeding. This technique will be useful to study contractile activity and regional patterns along the gastrointestinal tract under physiological conditions.

Detecting the effects of a standardized meal challenge on small bowel motility with MRI in prepared and unprepared bowel.

OBJECTIVE: MRI is increasingly used to evaluate small bowel contractility. The objective of this study was to validate a clinically practical stimulation test (300-kcal meal) for small bowel motility. METHODS: Thirty-one healthy subjects underwent dynamic MRI to capture global small bowel motility after ±10h fasting, of which 15 underwent bowel preparation consisting of 1 L 2.5% mannitol solution and 16 did not. Each subject underwent (1) a baseline motility scan (2) a food challenge (3) a post-challenge scan, and (4) second post-challenge scan (after ±20 minutes). This protocol was repeated within 2 weeks. Motility was quantified using a validated motility assessment technique. KEY RESULTS: Motility in prepared subjects at baseline was significantly higher than motility in unprepared subjects (0.36 AU vs 0.18 AU, P < 0.001). In the prepared group, the food challenge produced an 8% increase in motility (P = 0.33) while in the unprepared subjects a significant increase of 30% was observed (P < 0.001). Responses to food remained insignificant (P = 0.21) and significant (P = 0.003), for the prepared and unprepared subjects, respectively, ±20 minutes post food challenge. These results were confirmed in the repeated scan session. CONCLUSION & INFERENCES: A significant response to a 300-kcal meal was measured within 10 minutes in unprepared bowel, supporting the clinical use of this challenge to provoke and assess motility changes. A caloric challenge did not produce an observable increase in motility in mannitol prepared subjects.

Quantified Terminal Ileal Motility during MR Enterography as a Biomarker of Crohn Disease Activity: Prospective Multi-Institution Study.

Purpose To evaluate the accuracy of MRI-quantified small bowel motility for Crohn disease activity against endoscopic and histopathologic reference standards. Materials and Methods For this prospective study, 82 participants (median age, 31 years; range, 16 to 70 years; 42 males [median age, 31 years; range, 17 to 70 years] and 40 females [median age, 31 years; range, 16 to 63 years) underwent colonoscopy and MR enterography within 14 days (from October 2011 to March 2014) at two centers. The Crohn disease endoscopic index of severity (CDEIS), histopathologic activity score (endoscopic biopsy acute histologic inflammatory score [EAIS]), and MR index of activity (MaRIA) were scored in the terminal ileum. Terminal ileal motility was quantified by using an image registration based-motility assessment algorithm (hereafter, Motility). Sensitivity and specificity of Motility (˂0.3 arbitrary units) and MaRIA (≥7 and ≥11) for disease activity (CDEIS ≥4 or EAIS ≥1) were compared by using the McNemar test. Receiver operating characteristic curves were constructed and areas under the curve were compared. Motility was correlated with reference standards by using Spearman rank estimates. Results Terminal ileal Motility was negatively correlated with EAIS (r =-0.61; 95% confidence interval [CI]: 0.7, -0.5) and CDEIS (r = -0.59; 95% CI: 0.7, -0.4). With CDEIS as the standard of reference, Motility had higher sensitivity than did MaRIA (≥11) (93% vs 78%, respectively; P = .03), but lower specificity (61% vs 81%, respectively; P = .04). With EAIS as the standard of reference, Motility had higher sensitivity than did MaRIA (≥7) (92% vs 75%, respectively; P = .03) but similar specificity (71% vs 74%, respectively; P >.99). The area under the receiver operating characteristic curve for Motility was 0.86 and 0.87 with CDEIS and EAIS as the standard of reference, respectively. Conclusion The terminal ileal Motility score showed good agreement with endoscopic and histopathologic activity in Crohn disease. © RSNA, 2018 Online supplemental material is available for this article.

Relationship between MRI quantified small bowel motility and abdominal symptoms in Crohn's disease patients-a validation study.

OBJECTIVE: Previous single-centre MRI data suggests an inverse correlation between normal small bowel motility variance and abdominal symptoms in Crohn's disease (CD) patients. The current work prospectively assesses this observation in a larger, two-centre study. METHODS: MR enterography datasets were analysed from 82 patients (38 male, aged 16-68), who completed a contemporaneous Harvey-Bradshaw index (HBI) questionnaire. Dynamic "cine motility" breath-hold balanced steady-state free precession sequences were acquired through the whole small bowel (SB) volume. Regions of interest (ROIs) were manually applied to encompass all morphologically normal SB (i.e. excluding Crohn's affected bowel) and a validated registration technique used to produce motility maps. Mean and variance motility metrics were correlated with HBI and symptom components (well-being, pain and diarrhoea) using Spearman's correlation statistics. RESULTS: Overall, motility variance was non-significantly negatively correlated with the total HBI score, (r = -0.17, p = 0.12), but for subjects with a HBI score over 10, the negative correlation was significant (r = -0.633, p = 0.027). Motility variance was negatively correlated with diarrhoea (r = -0.29, p < 0.01). No significant correlation was found between mean motility and HBI (r = -0.02, p = 0.84). CONCLUSION: An inverse association between morphologically normal small bowel motility variance and patient symptoms has been prospectively confirmed in patients with HBI scores above 10. This association is particularly apparent for the symptom of diarrhoea. Advances in knowledge: This study builds on preliminary work by confirming in a large, well-controlled prospective multicentre study a relationship between normal bowel motility variance and patient reported symptoms which may have implications for drug development and clinical management.