McCallum, Richard W.

ABSTRACT Background Patients with gastroparesis (Gp) can have a variety of symptoms. Apart from use of prokinetics, symptomatic therapies for the predominant symptom (PrS) are used. Aims (1) To classify Gp patients based on their PrS; (2) To determine differences in Gp symptoms, gastric emptying (GE), quality of life (QOL), treatments, and symptom improvement among Gp patients with different PrS. Methods Gp patients were enrolled in a multicenter registry and followed for 96‐weeks. Patients recorded their PrS and completed questionnaires assessing symptoms and QOL at enrollment and at follow up visits. Results Of 1013 Gp patients (361 diabetic, 607 idiopathic, 45 post‐fundoplication), the PrS were nausea (31%), vomiting (20%), abdominal pain (20%), bloating (9%), fullness (4%), GERD (4%), constipation (3%). Abdominal pain was more often a PrS in idiopathics, whereas vomiting was more often a PrS in diabetics. QOL scores were lower in the abdominal pain PrS group. PrS was associated with greater use of directed symptomatic treatment (antiemetic agents and gastric electrical stimulation for nausea and vomiting, prokinetic agents for vomiting and fullness, and constipation medications for constipation). Of 555 patients followed over 48 weeks, GCSI improved by ≥ 1 in 26% overall, more often in patients with initial PrS of nausea (32%) and bloating (35%) and less often for initial PrS of fullness (13%) or abdominal pain (15%). Conclusions In Gp patients, the most common PrS were nausea, vomiting, and abdominal pain. PrS is associated with QOL, treatments utilized, and patient outcomes. Thus, the PrS of a patient with Gp provides useful information about their present condition and future outcome.

ABSTRACTIntroductionStudies demonstrate an overlap of constipation with gastroparesis and functional dyspepsia, but the impact of treatments that target constipation on improving upper gastrointestinal (UGI) symptoms is unexplored. We quantified the effects of constipation medication therapies on UGI and constipation symptom severity in subjects presenting with symptoms of gastroparesis.MethodsFifty‐six subjects with symptoms of gastroparesis underwent concurrent wireless motility capsule and gastric emptying scintigraphy and were recommended to receive either a new medication therapy for constipation or a change in constipation therapy based on investigator interpretation of test results. Gastroparesis Cardinal Symptom Index (GCSI), upper abdominal pain, and constipation scores were compared between baseline and 6 months. Data were compared between delayed or non‐delayed gastric emptying and the presence or absence of slow colonic transit.Key ResultsSubjects with slow colonic transit had improvements in GCSI (p = 0.007) and constipation scores (p = 0.004) after treatment with a new or changed constipation medication, with the delayed emptying subgroup driving GCSI improvements (p = 0.004). Reductions in nausea/vomiting (p = 0.02) and early satiety/fullness subscores (p = 0.002) with trends to improved bloating/distention subscores (p = 0.06) were observed in this subgroup, but upper abdominal pain was unchanged. Subjects with normal colonic transit showed no improvement in GCSI scores regardless of gastric emptying status (p > 0.05).Conclusions and InferencesIdentifying and treating delayed colonic transit in gastroparetic (delayed gastric emptying) subjects improves global UGI symptoms as well as selected individual symptoms. Evaluation of whole gut motility as well as recognizing and managing extragastric delay may promote improved outcomes in these patients.Trial RegistrationClinicalTrials.gov: NCT02022826

INTRODUCTION: Pharmacologic therapies for symptoms of gastroparesis (GP) have limited efficacy, and it is difficult to predict which patients will respond. In this study, we implemented a machine learning model to predict the response to prokinetics and/or neuromodulators in patients with GP-like symptoms. METHODS: Subjects with suspected GP underwent simultaneous gastric emptying scintigraphy (GES) and wireless motility capsule and were followed for 6 months. Subjects were included if they were started on neuromodulators and/or prokinetics. Subjects were considered responders if their GP Cardinal Symptom Index at 6 months decreased by ≥1 from baseline. A machine learning model was trained using lasso regression, ridge regression, or random forest. Five-fold cross-validation was used to train the models, and the area under the receiver operator characteristic curve (AUC-ROC) was calculated using the test set. RESULTS: Of the 150 patients enrolled, 123 patients received either a prokinetic and/or a neuromodulator. Of the 123, 45 were considered responders and 78 were nonresponders. A ridge regression model with the variables, such as body mass index, infectious prodrome, delayed gastric emptying scintigraphy, no diabetes, had the highest AUC-ROC of 0.72. The model performed well for subjects on prokinetics without neuromodulators (AUC-ROC of 0.83) but poorly for those on neuromodulators without prokinetics. A separate model with gastric emptying time, duodenal motility index, no diabetes, and functional dyspepsia performed better (AUC-ROC of 0.75). DISCUSSION: This machine learning model has an acceptable accuracy in predicting those who will respond to neuromodulators and/or prokinetics. If validated, our model provides valuable data in predicting treatment outcomes in patients with GP-like symptoms.

AbstractBackgroundGastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.ObjectiveGenetic predisposition may play a role; however, investigation at the genome‐wide level has not been performed.MethodsWe carried out a genome‐wide association study (GWAS) meta‐analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population‐based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non‐gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high‐quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene‐set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls.ResultsWhile no SNP associations were detected at strict significance (p ≤ 5 × 10−8), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10−5), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10−7) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein‐coding candidate genes. Gene‐set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin‐Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls).ConclusionWe report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory‐motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.

IMD0 and WLST were assessed for their clinical utility in assessing patients with symptoms of gastroparesis. Low IMD0 is associated with less gastric retention and less heartburn. Volume of water consumed during WLST, while associated with IMD0, has associations with early satiety, postprandial fullness, loss of appetite, and nausea. IMD0 and WLST appear to overlap somewhat in their assessment of gastric physiology in adults with symptoms of gastroparesis but relate to different dyspeptic symptoms.

Summary Background Patients with gastroparesis and related disorders have symptoms including early satiety, postprandial fullness and bloating. Buspirone, a 5‐HT 1 receptor agonist, may improve fundic accommodation. Aim To determine if buspirone treatment improves early satiety and postprandial fullness in patients with symptoms of gastroparesis. Methods This 4‐week multi‐centre clinical trial randomised patients with symptoms of gastroparesis and moderate‐to‐severe symptoms of fullness (Gastroparesis Cardinal Symptom Index [GCSI] early satiety/postprandial fullness subscore [ES/PPF]) to buspirone (10 mg orally) or placebo three times per day. The primary outcome was a change in the ES/PPF from baseline to 4 weeks. The primary analysis was per protocol intention‐to‐treat ANCOVA of between‐group baseline vs. 4‐week differences (DoD) in ES/PPF adjusted for baseline ES/PPF. Results are reported using both nominal and Bonferroni (BF) p values. Results and conclusions Ninety‐six patients (47 buspirone, 49 placeboes; 92% female, 50% delayed gastric emptying, 39% diabetic) were enrolled. There was no between‐groups difference in the 4‐week ES/PPF primary outcome: −1.16 ± 1.25 (SD) on buspirone vs −1.03 ± 1.29 (SD) on placebo (mean DoD: −0.11 [95% CI: −0.68, 0.45]; p = 0.69). Buspirone performed better than placebo in patients with severe‐to‐very severe bloating at baseline compared to patients with none to moderate: (ES/PPF DoD = −0.65 vs. 1.58, p TX*GROUP = 0.003; p BF = 0.07). Among individual GCSI symptoms, only bloating appeared to improve with buspirone vs. placebo. Conclusions Patients with moderate‐to‐severe early satiety/postprandial fullness and other symptoms of gastroparesis did not benefit from buspirone treatment to improve the ES/PPF primary outcome compared with placebo. There was a suggestion of the benefit of buspirone in patients with more severe bloating. Trial Registration: ClinicalTrials.gov NCT0358714285.

AbstractBackgroundPatients with gastroparesis (Gp) may need enteral nutrition (EN) or exclusive parenteral nutrition (PN). Among patients with Gp, we aimed to (1) identify the frequency of EN and exclusive PN use and (2) explore characteristics of patients using EN and/or exclusive PN compared with those using oral nutrition (ON), including changes over 48 weeks.MethodsPatients with Gp underwent history and physical examination, gastric emptying scintigraphy, water load satiety testing (WLST), and questionnaires assessing gastrointestinal symptoms and quality of life (QOL). Patients were observed 48 weeks.ResultsOf 971 patients with Gp (idiopathic, 579; diabetic, 336; post–Nissen fundoplication, 51), 939 (96.7%) were using ON only, 14 (1.4%) using exclusive PN, and 18 (1.9%) using EN. Compared with patients receiving ON, patients receiving exclusive PN and/or EN were younger, had lower body mass index, and had greater symptom severity. Patients receiving exclusive PN and/or EN had lower physical QOL but not mental QOL or Gp‐related QOL scores. Patients receiving exclusive PN and/or EN ingested less water during WLST but did not have worse gastric emptying. Of those who had been receiving exclusive PN and/or EN, 50% and 25%, respectively, resumed ON at 48‐week follow‐up.ConclusionsThis study describes patients with Gp requiring exclusive PN and/or EN for nutrition support, who represent a small (3.3%) but important subset of patients with Gp. Unique clinical and physiological parameters are associated with this subset and provide insight into the use of nutrition support in Gp.

Patients with delayed and normal gastric emptying (GE) had similar symptom profiles during gastric emptying scintigraphy (GES). Idiopathic patients with symptoms of gastroparesis had less gastric retention by GES; but more symptoms after GES meal and after water load satiety test (WLST) compared with diabetic patients. In patients with symptoms of gastroparesis, symptoms after WLST increased with decreasing water consumption. Early satiety and loss of appetite were associated with decreased water consumption during WLST. Thus, impaired accommodation and perhaps visceral hypersensitivity are important in explaining postprandial symptoms in gastroparesis.