Yates, Katherine P.

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.

AbstractBackgroundUnderstanding factors that impair quality of life (QOL) in gastroparesis is important for clinical management. Aims: (a) Determine QOL in patients with gastroparesis; (b) Determine factors that impair QOL.MethodsGastroparetic patientsAQ6 underwent history and questionnaires assessing symptoms (PAGI‐SYM and Rome III), QOL (SF‐36v2 and PAGI‐QOL), depression (Beck Depression Inventory [BDI]), and anxiety (State Trait Anxiety InventoryAQ7).Key Results715 gastroparesis patients (256 diabetic (DG), 459 idiopathic (IG)) were evaluated. SF‐36 physical component (PC) score averaged 33.3 ± 10.5; 41% had impaired score <30. SF‐36 PC scores were similar between diabetic and idiopathic gastroparesis. Impaired SF‐36 PC associated with increased nausea/vomiting and upper abdominal pain subscores, acute onset of symptoms, higher number of comorbidities, use of narcotic pain medications, and irritable bowel syndrome (IBS). SF‐36 mental component (MC) score averaged 38.9 ± 13.0; 26% had impaired score <30. Poor SF‐36 MC associated with diabetic etiology, higher Beck depression inventory, and state anxiety scores. PAGI‐QOL score averaged 2.6 ± 1.1; 50% had a score of <2.6. Low PAGI‐QOL associated with higher fullness, bloating, and upper abdominal pain subscores, more depression and Trait anxiety, smoking cigarettes, need for nutritional support, progressively worsening symptoms and periodic exacerbations.Conclusions & InferencesMultiple measures show poor QOL present in gastroparesis. Several areas impacted on reduced QOL: (a) Symptoms of nausea, vomiting, and abdominal pain, as well as IBS; (b) Etiology and acute onset and progressively worsening symptoms; (c) Comorbidities and psychological factors such as anxiety and depression; (d) Patient‐related factors such as smoking. Targeting the modifiable factors may improve patient outcomes in gastroparesis.

Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, “Role of Macrophages, Fibroblasts and Endothelial Cells” was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10−9; IG FDR = 6.3 × 10−12]. In DG, properdin expression correlated with GCSI bloating ( r = −0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-ζ type, and complement C2 correlated with 4 h gastric retention ( r = −0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis. NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.

Aberrant hepatocyte Notch activation is required for development of NASH-associated fibrosis, and Notch inhibition ameliorates obesity-induced liver disease.

Abstract Background In studies of diabetic gastroparesis, patients with type 1 and type 2 diabetes mellitus (T1 DM , T2 DM ) are often combined for analyses. We compared gastroparesis severity, healthcare utilization, psychological function, and quality of life in T1 DM vs T2 DM gastroparesis patients. Methods Questionnaire, laboratory, and scintigraphy data from patients with gastroparesis and T1 DM and T2 DM from seven centers of the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Registry were compared at enrollment and after 48 weeks. Multiple regression models assessed baseline and follow‐up differences between diabetes subtypes. Key Results At baseline, T1 DM patients ( N = 78) had slower gastric emptying, more hospitalizations, more gastric stimulator implantations, higher hemoglobin A1c (HbA1c), and more anxiety vs T2 DM patients ( N = 59). Independent discriminators of patients with T1 DM vs T2 DM included worse gastroesophageal reflux disease, less bloating, more peripheral neuropathy, and fewer comorbidities ( p ≤ 0.05). On follow‐up, gastrointestinal ( GI ) symptom scores decreased only in T2 DM ( p < 0.05), but not in T1 DM patients who reported greater prokinetic, proton pump inhibitor, anxiolytic, and gastric stimulator usage over 48 weeks ( p ≤ 0.03). Gastrointestinal symptoms at baseline and 48 weeks with both subtypes were not associated with HbA1c, peripheral neuropathy, psychological factors, or quality of life. Conclusions & Inferences Baseline symptoms were similar in T1 DM and T2 DM patients, even though T1 DM patients had worse gastric emptying delays and higher HbA1c suggesting other factors mediate symptom severity. Symptom scores at 48 weeks decreased in T2 DM , but not T1 DM patients, despite increased medical and surgical treatment utilization by T1 DM patients. Defining causes of different outcomes in diabetic gastroparesis warrants further investigation.

Postmenopausal women with nonalcoholic steatohepatitis are at an increased risk of hepatic fibrosis compared with premenopausal women. Whether duration of estrogen deficiency in postmenopausal state dictates an individual's fibrosis risk remains uninvestigated. We assessed the associations of age at menopause and time from menopause with fibrosis severity in postmenopausal women with nonalcoholic fatty liver disease. Data from 488 postmenopausal women with (1) histologic diagnosis of nonalcoholic fatty liver disease and (2) self‐reported information on age at menopause were analyzed. The associations of premature menopause (age at menopause of <40 years) and time from menopause (age at study enrollment ‐ age at menopause, years) with fibrosis severity (stage 0‐4) were assessed using multiple ordinal logistic regression models with and without adjusting for clinical confounders. Among the participants (age at menopause 43.7 ± 8.6 years), women with premature menopause (29.3%) were younger at enrollment ( P < 0.001) and used hormone replacement therapy more often ( P < 0.003). After adjusting for age at enrollment, race, waist circumference standardized by body mass index, current smoking, current alcohol use, hypertension, diabetes/impaired fasting glucose, homeostatic model assessment of insulin resistance, and hormone replacement therapy, premature menopause was associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio = 1.9, 95% confidence interval 1.3‐2.7, P = 0.001), while time from menopause was directly associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio for 5‐year unit = 1.2, 95% confidence interval 1.1‐1.3, P = 0.002). Conclusion : Duration of estrogen deficiency in postmenopausal state confers fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. (H epatology 2016;64:85–91)

ABSTRACTObjectives:In adults, vitamin D deficiency is common in patients with nonalcoholic fatty liver disease (NAFLD) and has been associated with the severity of histology. There are known differences between adult and pediatric NAFLD, with little data regarding the relation between vitamin D and pediatric NAFLD. The aim of the present study was to examine the relation between vitamin D levels and NAFLD in children.Methods:Clinical and histological data were used from children ages 2 to 18 years with biopsy‐proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network studies. 25(OH) vitamin D levels were measured from serum. Data examined included demographics, anthropometrics, laboratory markers, and liver histology. Data were analyzed using 3 categories of vitamin D level: deficient (≤20 ng/mL), insufficient (21–29 ng/mL), and sufficient (≥30 ng/mL).Results:A total of 102 children were studied. There was a high prevalence (80/102, 78%) of vitamin D deficiency or insufficiency; however, there were no significant associations between vitamin D level and the histological characteristics or severity of NAFLD. Significantly higher levels of triglycerides were found in those with vitamin D deficiency (P = 0.004), but there was no association with other features of the metabolic syndrome.Conclusions:There is a high prevalence of vitamin D deficiency and insufficiency in children with biopsy‐proven NAFLD; however, no association was found between vitamin D deficiency and the severity of disease on biopsies. This differs from adult NAFLD studies in which vitamin D deficiency correlates with histological severity, suggesting differences in the risk factors for or consequences of pediatric NAFLD.