Autonomic function in gastroparesis and chronic unexplained nausea and vomiting: Relationship with etiology, gastric emptying, and symptom severity.

BACKGROUND: Autonomic dysfunction can be present in patients with idiopathic and diabetic gastroparesis. The role of autonomic dysfunction relating to gastric emptying and upper gastrointestinal symptoms in patients with gastroparesis and chronic unexplained nausea and vomiting (CUNV) remains unclear. The aim of our study is to evaluate autonomic function in patients with gastroparesis and CUNV with respect to etiology, gastric emptying and symptom severity. METHODS: We studied 242 patients with chronic gastroparetic symptoms recruited at eight centers. All patients had a gastric emptying scintigraphy within 6 months of the study. Symptom severity was assessed using the gastroparesis cardinal symptom index. Autonomic function testing was performed at baseline enrollment using the ANX 3.0 autonomic monitoring system which measures heart rate variability and respiratory activity measurements. KEY RESULTS: Low sympathetic response to challenge (Valsalva or standing) was the most common abnormality seen impacting 89% diabetic and 74% idiopathic patients. Diabetics compared to idiopathics, exhibited greater global hypofunction with sympathetic (OR = 4.7, 95% CI 2.2-10.3; P < .001) and parasympathetic (OR = 7.2, 95% CI 3.4-15.0; P < .001) dysfunction. Patients with delayed gastric emptying were more likely to have paradoxic parasympathetic excessive during sympathetic challenge [(Valsalva or standing) 40% vs. 26%, P = .05]. Patients with more severe symptoms exhibited greater parasympathetic dysfunction compared to those with mild-moderate symptoms: resting sympathovagal balance [LFa/RFa 1.8 (1.0-3.1) vs. 1.2 (0.6-2.3), P = .006)] and standing parasympathetic activity [0.4 (0.1-0.8) vs. 0.6 (0.2-1.7); P = .03]. CONCLUSIONS: Autonomic dysfunction was common in patients with gastroparesis and CUNV. Parasympathetic dysfunction was associated with delayed gastric emptying and more severe upper gastrointestinal symptoms. Conversely, sympathetic hypofunction was associated with milder symptoms. INFERENCES: Gastroparesis and CUNV may be a manifestation of GI autonomic dysfunction or imbalance, such that sympathetic dysfunction occurs early on in the manifestation of chronic upper GI symptoms, while parasympathetic dysfunction results in more severe symptoms and delayed gastric emptying.

Marijuana Use in Patients with Symptoms of Gastroparesis: Prevalence, Patient Characteristics, and Perceived Benefit.

BACKGROUND: Marijuana may be used by some patients with gastroparesis (Gp) for its potential antiemetic, orexigenic, and pain-relieving effects. AIMS: The aim of this study was to describe the use of marijuana by patients for symptoms of Gp, assessing prevalence of use, patient characteristics, and patients' perceived benefit on their symptoms of Gp. METHODS: Patients with symptoms of Gp underwent history and physical examination, gastric emptying scintigraphy, and questionnaires assessing symptoms. Patients were asked about the current use of medications and alternative medications including marijuana. RESULTS: Fifty-nine of 506 (11.7%) patients with symptoms of Gp reported current marijuana use, being similar among patients with delayed and normal gastric emptying and similar in idiopathic and diabetic patients. Patients using marijuana were younger, more often current tobacco smokers, less likely to be a college graduate, married or have income > $50,000. Patients using marijuana had higher nausea/vomiting subscore (2.7 vs 2.1; p = 0.002), higher upper abdominal pain subscore (3.5 vs 2.9; p = 0.003), more likely to be using promethazine (37 vs 25%; p = 0.05) and dronabinol (17 vs 3%; p < 0.0001). Of patients using marijuana, 51% had been using it for more than 2 years, 47% were using this once or more per day, and 81% of marijuana users rated their benefit from marijuana as better or much better. CONCLUSIONS: A subset of patients (12%) with symptoms of Gp use marijuana. Patients with severe nausea and abdominal pain were more likely to use marijuana and perceive it to be beneficial for their symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01696747.

Satiety testing in diabetic gastroparesis: Effects of insulin pump therapy with continuous glucose monitoring on upper gastrointestinal symptoms and gastric myoelectrical activity.

BACKGROUND: Symptoms induced by caloric or non-caloric satiety test meals and gastric myoelectrical activity (GMA) have not been studied in patients with diabetic gastroparesis (DGP) before and after intense glucose management. AIMS: We determined the effects of continuous subcutaneous insulin infusion (CSII) with continuous glucose monitoring (CGM) on GI symptoms, volume consumed, and GMA induced by the caloric meal satiety test (CMST) and water load satiety test (WLST) in DGP. METHODS: Forty-five patients with DGP underwent CMST and WLST at baseline and 24 weeks after CSII with CGM. Subjects ingested the test meals until they were completely full. Visual analog scales were used to quantify pre- and postmeal symptoms, and GMA was recorded with cutaneous electrodes and analyzed visually and by computer. KEY RESULTS: At baseline and 24-week visits, nausea, bloating, abdominal discomfort, and fullness were immediately increased after CMST and WLST (Ps < 0.01). The meal volumes ingested were significantly less than normal controls at both visits in almost one-third of the subjects. After the CMST, the percentage 3 cycle per minute GMA increased and bradygastria decreased compared with WLST (Ps < 0.05). After treatment for 24 weeks meal volumes ingested, postmeal symptoms and GMA were no different than baseline. CONCLUSIONS AND INFERENCES: (a) Satiety test meals elicited symptoms of nausea, bloating, and abdominal discomfort; (b) CMST stimulated more symptoms and changes in GMA than WLST; and (c) CSII with CGM for 24 weeks did not improve symptoms, volumes ingested, or GMA elicited by the two satiety test meals in these patients with diabetic GP. Satiety tests in diabetic gastropresis are useful to study acute postprandial symptoms and GMA, but these measures were not improved by intensive insulin therapy.

Delayed Gastric Emptying Associates With Diabetic Complications in Diabetic Patients With Symptoms of Gastroparesis.

OBJECTIVES: Diabetic gastroparesis (Gp) occurs more often in type 1 diabetes mellitus (T1DM) than in type 2 diabetes mellitus (T2DM). Other diabetic end-organ complications include peripheral neuropathy, nephropathy, and retinopathy (together termed triopathy). This study determines the prevalence of diabetic complications (retinopathy, nephropathy, and peripheral neuropathy) in diabetic patients with symptoms of Gp, assessing the differences between T1DM and T2DM and delayed and normal gastric emptying (GE). METHODS: Diabetic patients with symptoms of Gp underwent history and physical examination, GE scintigraphy, electrogastrography with water load, autonomic function testing, and questionnaires assessing symptoms and peripheral neuropathy. RESULTS: One hundred thirty-three diabetic patients with symptoms of Gp were studied: 59 with T1DM and 74 with T2DM and 103 with delayed GE and 30 without delayed GE. The presence of retinopathy (37% vs 24%; P = 0.13), nephropathy (19% vs 11%; P = 0.22), and peripheral neuropathy (53% vs 39%; P = 0.16) was not significantly higher in T1DM than in T2DM; however, triopathies (all 3 complications together) were seen in 10% of T1DM and 3% of T2DM (P = 0.04). Diabetic patients with delayed GE had increased prevalence of retinopathy (36% vs 10%; P = 0.006) and number of diabetic complications (1.0 vs 0.5; P = 0.009); however, 39% of diabetic patients with delayed GE did not have any diabetic complications. DISCUSSION: In diabetic patients with symptoms of Gp, delayed GE was associated with the presence of retinopathy and the total number of diabetic complications. Only 10% of patients with T1DM and 3% of those with T2DM had triopathy of complications, and 39% of diabetic patients with Gp did not have any diabetic complications. Thus, the presence of diabetic complications should raise awareness for Gp in either T1DM or T2DM; however, diabetic Gp frequently occurs without other diabetic complications.

Effectiveness of gastric electrical stimulation in gastroparesis: Results from a large prospectively collected database of national gastroparesis registries.

BACKGROUND: Gastric electrical stimulation (GES) for treating gastroparesis symptoms is controversial. METHODS: We studied 319 idiopathic or diabetic gastroparesis symptom patients from the Gastroparesis Clinical Research Consortium (GpCRC) observational studies: 238 without GES and 81 with GES. We assessed the effects of GES using change in GCSI total score and nausea/vomiting subscales between baseline and 48 weeks. We used propensity score methods to control for imbalances in patient characteristics between comparison groups. KEY RESULTS: GES patients were clinically worse (40% severe vs. 18% for non-GES; P < .001); worse PAGI-QOL (2.2. vs. 2.6; P = .003); and worse GCSI total scores (3.5 vs. 2.8; P < .001). We observed improvements in 48-week GCSI total scores for GES vs. non-GES: improvement by ≥ 1-point (RR = 1.63; 95% CI = (1.14, 2.33); P = .01) and change from enrollment (difference = -0.5 (-0.8, -0.3); P < .001). When adjusting for patient characteristics, symptom scores were smaller and not statistically significant: improvement by ≥ 1-point (RR = 1.29 (0.88, 1.90); P = .20) and change from the enrollment (difference = -0.3 (-0.6, 0.0); P = .07). Of the individual items, the nausea improved by ≥ 1 point (RR = 1.31 (1.03, 1.67); P = .04). Patients with GCSI score ≥ 3.0 tended to improve more than those with score < 3.0. (Adjusted P = 0.02). CONCLUSIONS AND INFERENCES: This multicenter study of gastroparesis patients found significant improvements in gastroparesis symptoms among GES patients. Accounting for imbalances in patient characteristics, only nausea remained significant. Patients with greater symptoms at baseline improved more after GES. A much larger sample of patients is needed to fully evaluate symptomatic responses and to identify patients likely to respond to GES.

Abdominal Pain in Patients with Gastroparesis: Associations with Gastroparesis Symptoms, Etiology of Gastroparesis, Gastric Emptying, Somatization, and Quality of Life.

Abdominal pain can be an important symptom in some patients with gastroparesis (Gp). AIMS: (1) To describe characteristics of abdominal pain in Gp; (2) describe Gp patients reporting abdominal pain. METHODS: Patients with idiopathic gastroparesis (IG) and diabetic gastroparesis (DG) were studied with gastric emptying scintigraphy, water load test, wireless motility capsule, and questionnaires assessing symptoms [Patient Assessment of Upper GI Symptoms (PAGI-SYM) including Gastroparesis Cardinal Symptom Index (GCSI)], quality of life (PAGI-QOL, SF-36), psychological state [Beck Depression Inventory (BDI), State-Trait Anxiety Index (STAI), PHQ-15 somatization scale]. RESULTS: In total, 346 Gp patients included 212 IG and 134 DG. Ninety percentage of Gp patients reported abdominal pain (89% DG and 91% IG). Pain was primarily in upper or central midline abdomen, described as cramping or sickening. Upper abdominal pain was severe or very severe on PAGI-SYM by 116/346 (34%) patients, more often by females than by males, but similarly in IG and DG. Increased upper abdominal pain severity was associated with increased severity of the nine GCSI symptoms, depression on BDI, anxiety on STAI, somatization on PHQ-15, the use of opiate medications, decreased SF-36 physical component, and PAGI-QOL, but not related to severity of delayed gastric emptying or water load ingestion. Using logistic regression, severe/very severe upper abdominal pain associated with increased GCSI scores, opiate medication use, and PHQ-15 somatic symptom scores. CONCLUSIONS: Abdominal pain is common in patients with Gp, both IG and DG. Severe/very severe upper abdominal pain occurred in 34% of Gp patients and associated with other Gp symptoms, somatization, and opiate medication use. ClinicalTrials.gov Identifier: NCT01696747.

Ethnic, Racial, and Sex Differences in Etiology, Symptoms, Treatment, and Symptom Outcomes of Patients With Gastroparesis.

BACKGROUND & AIMS: Gastroparesis is a chronic disorder of the stomach characterized by nausea, vomiting, early satiety, postprandial fullness, and abdominal pain. There is limited information on gastroparesis in minority populations. We assessed ethnic, racial, and sex variations in the etiology, symptoms, quality of life, gastric emptying, treatments, and symptom outcomes of patients with gastroparesis. METHODS: We collected information from the National Institutes of Health Gastroparesis Consortium on 718 adult patients, from September 2007 through December 2017. Patients were followed every 4 or 6 months, when data were collected on medical histories, symptoms (based on answers to the PAGI-SYM questionnaires), and quality of life (based on SF-36). Follow-up information collected at 1 year (48 week) was used in this analysis. Comparisons were made between patients of self-reported non-Hispanic white, non-Hispanic black, and Hispanic ethnicities, as well as and between male and female patients. RESULTS: Our final analysis included 552 non-Hispanic whites (77%), 83 persons of Hispanic ethnicity (12%), 62 non-Hispanic blacks (9%), 603 women (84%), and 115 men (16%). A significantly higher proportion of non-Hispanic blacks (60%) had gastroparesis of diabetic etiology than of non-Hispanic whites (28%); non-Hispanic blacks also had more severe retching (2.5 vs 1.7 score) and vomiting (2.9 vs 1.8 score) and a higher percentage were hospitalized in the past year (66% vs 38%). A significantly higher proportion of Hispanics had gastroparesis of diabetic etiology (59%) than non-Hispanic whites (28%), but Hispanics had less-severe nausea (2.7 vs 3.3 score), less early satiety (3.0 vs 3.5 score), and a lower proportion used domperidone (8% vs 21%) or had a peripherally inserted central catheter (1% vs 7%). A higher proportion of women had gastroparesis of idiopathic etiology (69%) than men (46%); women had more severe symptoms of stomach fullness (3.6 vs 3.1 score), early satiety (3.5 vs 2.9 score), postprandial fullness (3.7 vs 3.1 score), bloating (3.3 vs 2.6 score), stomach visibly larger (3.0 vs 2.1 score), and upper abdominal pain (2.9 vs 2.4 score). A lower proportion of women were hospitalized in past year (39% vs 53% of men). CONCLUSIONS: In patients with gastroparesis, etiologies, symptom severity, and treatments vary among races and ethnicities and between sexes. ClinicalTrials.gov Identifier: NCT01696747.

Opioid Use and Potency Are Associated With Clinical Features, Quality of Life, and Use of Resources in Patients With Gastroparesis.

BACKGROUND & AIMS: Many patients with gastroparesis are prescribed opioids for pain control, but indications for opioid prescriptions and the relationship of opioid use to gastroparesis manifestations are undefined. We characterized associations of use of potent vs weaker opioids and presentations of diabetic and idiopathic gastroparesis. METHODS: We collected data on symptoms, gastric emptying, quality of life, and health care resource use from 583 patients with gastroparesis (>10% 4-h scintigraphic retention) from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Consortium, from January 2007 through November 2016. Patients completed medical questionnaires that included questions about opioid use. The opioid(s) were categorized for potency relative to oral morphine. Symptom severities were quantified by Patient Assessment of Upper Gastrointestinal Disorders Symptoms questionnaires. Subgroup analyses compared patients on potent vs weaker opioids and opioid effects in diabetic vs idiopathic etiologies. RESULTS: Forty-one percent of patients were taking opioids; 82% of these took potent agents (morphine, hydrocodone, oxycodone, methadone, hydromorphone, buprenorphine, or fentanyl). Abdominal pain was the reason for prescription for 61% of patients taking opioids. Mean scores for gastroparesis, nausea/vomiting, bloating/distention, abdominal pain, and constipation scores were higher in opioid users (P ≤ .05). Opioid use was associated with greater levels of gastric retention, worse quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications compared with nonusers (P ≤ .03). Use of potent opioids was associated with worse gastroparesis, nausea/vomiting, upper abdominal pain, and quality-of-life scores, and more hospitalizations compared with weaker opioids (tapentadol, tramadol, codeine, or propoxyphene) (P ≤ .05). Opioid use was associated with larger increases in gastric retention in patients with idiopathic vs diabetic gastroparesis (P = .008). CONCLUSIONS: Opioid use is prevalent among patients with diabetic or idiopathic gastroparesis, and is associated with worse symptoms, delays in gastric emptying, and lower quality of life, as well as greater use of resources. Potent opioids are associated with larger effects than weaker agents. These findings form a basis for studies to characterize adverse outcomes of opioid use in patients with gastroparesis and to help identify those who might benefit from interventions to prevent opioid overuse.

Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis.

BACKGROUND: Cellular changes described in human gastroparesis have revealed a role for immune dysregulation, however, a mechanistic understanding of human gastroparesis and the signaling pathways involved are still unclear. METHODS: Diabetic gastroparetics, diabetic non-gastroparetic controls, idiopathic gastroparetics and non-diabetic non-gastroparetic controls underwent full-thickness gastric body biopsies. Deep RNA sequencing was performed and pathway analysis of differentially expressed transcripts was done using Ingenuity®. A subset of differentially expressed genes in diabetic gastroparesis was validated in a separate cohort using QT-PCR. RESULTS: 111 genes were differentially expressed in diabetic gastroparesis and 181 in idiopathic gastroparesis with a log2fold difference of | ≥ 2| and false detection rate (FDR) < 5%. Top canonical pathways in diabetic gastroparesis included genes involved with macrophages, fibroblasts and endothelial cells in rheumatoid arthritis, osteoarthritis pathway and differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F. Top canonical pathways in idiopathic gastroparesis included genes involved in granulocyte adhesion and diapedesis, agranulocyte adhesion and diapedesis, and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Sixty-five differentially expressed genes (log2fold difference | ≥ 2|, FDR < 5%) were common in both diabetic and idiopathic gastroparesis with genes in the top 5 canonical pathways associated with immune signaling. 4/5 highly differentially expressed genes (SGK1, APOLD1, CXCR4, CXCL2, and FOS) in diabetic gastroparesis were validated in a separate cohort of patients using RT-PCR. Immune profile analysis revealed that genes associated with M1 (pro inflammatory) macrophages were enriched in tissues from idiopathic gastroparesis tissues compared to controls (p < 0.05). CONCLUSIONS: Diabetic and idiopathic gastroparesis have both unique and overlapping transcriptomic signatures. Innate immune signaling likely plays a central role in pathogenesis of human gastroparesis.

Glucose sensor-augmented continuous subcutaneous insulin infusion in patients with diabetic gastroparesis: An open-label pilot prospective study.

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85-1.64, P = 0.33). CGM time in hypoglycemia (<70 mg/dL) decreased from 3.9% to 1.8% (P<0.0001), time in euglycemia (70-180 mg/dL) increased from 44.0% to 52.0% (P = 0.02), time in severe hyperglycemia (>300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P<0.0001) and volumes of liquid nutrient meals tolerated increased from 420±258 to 487±312 mL (P = 0.05) at 24 weeks. In conclusion, CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis.

Islet Cell Associated Autoantibodies and C-Peptide Levels in Patients with Diabetes and Symptoms of Gastroparesis.

INTRODUCTION: Individuals with diabetes are at increased risk for complications, including gastroparesis. Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting in decreased beta-cell function. Glutamic acid decarboxylase-65 antibody (GADA) is the most commonly used test to assess autoimmunity while C-peptide level is used to assess beta-cell function. Patients with type 2 diabetes mellitus (T2DM), who are GADA positive, are labeled latent autoimmune diabetes in adults (LADA). OBJECTIVE: To characterize patients with T1 and T2DM who have symptoms of gastroparesis using GADA and C-peptide levels and to look for association with the presence of gastroparesis and its symptom severity. DESIGN: 113 T1DM and 90 T2DM patients with symptoms suggestive of gastroparesis were studied. Symptom severity was assessed using Gastroparesis Cardinal Symptom Index (GCSI). Serum samples were analyzed for GADA and C-peptide. RESULTS: Delayed gastric emptying was present in 91 (81%) of T1DM and 60 (67%) of T2DM patients (p = 0.04). GADA was present in 13% of T2DM subjects [10% in delayed gastric emptying and 20% in normal gastric emptying (p = 0.2)]. Gastric retention and GCSI scores were mostly similar in GADA positive and negative T2DM patients. GADA was present in 45% of T1DM subjects [46% in delayed gastric emptying and 41% in normal gastric emptying (p = 0.81)]. Low C-peptide levels were seen in 79% T1DM patients and 8% T2DM. All seven T2DM patients with low C-peptide were taking insulin compared to 52% of T2DM with normal C-peptide. CONCLUSION: GADA was present in 13% while low C-peptide was seen in 8% of our T2DM patients with symptoms of gastroparesis. Neither did correlate with degree of delayed gastric emptying or symptom severity. CLINICALTRIALSGOV IDENTIFIER: NCT01696747.

Aprepitant Has Mixed Effects on Nausea and Reduces Other Symptoms in Patients With Gastroparesis and Related Disorders.

BACKGROUND & AIMS: There are few effective treatments for nausea and other symptoms in patients with gastroparesis and related syndromes. We performed a randomized trial of the ability of the neurokinin-1 receptor antagonist aprepitant to reduce symptoms in patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome. METHODS: We conducted a 4-week multicenter, double-masked trial of 126 patients with at least moderate symptoms of chronic nausea and vomiting of presumed gastric origin for a minimum of 6 months. Patients were randomly assigned to groups given oral aprepitant (125 mg/day, n = 63) or placebo (n = 63). The primary outcome from the intention-to-treat analysis was reduction in nausea, defined as a decrease of 25 mm or more, or absolute level below 25 mm, on a daily patient-reported 0-to-100 visual analog scale (VAS) of nausea severity. We calculated relative risks of nausea improvement using stratified Cochran-Mental-Haenszel analysis. RESULTS: Aprepitant did not reduce symptoms of nausea, based on the primary outcome measure (46% reduction in the VAS score in the aprepitant group vs 40% reduction in the placebo group; relative risk, 1.2; 95% CI, 0.8-1.7) (P = .43). However, patients in the aprepitant group had significant changes in secondary outcomes such as reduction in symptom severity (measured by the 0-5 Gastroparesis Clinical Symptom Index) for nausea (1.8 vs 1.0; P = .005), vomiting (1.6 vs 0.5; P = .001), and overall symptoms (1.3 vs 0.7; P = .001). Adverse events, predominantly mild or moderate in severity grade, were more common in aprepitant (22 of 63 patients, 35% vs 11 of 63, 17% in the placebo group) (P = .04). CONCLUSIONS: In a randomized trial of patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome, aprepitant did not reduce the severity of nausea when reduction in VAS score was used as the primary outcome. However, aprepitant had varying effects on secondary outcomes of symptom improvement. These findings support the need to identify appropriate patient outcomes for trials of therapies for gastroparesis, including potential additional trials for aprepitant. ClinicalTrials.gov no: NCT01149369.

Intragastric Meal Distribution During Gastric Emptying Scintigraphy for Assessment of Fundic Accommodation: Correlation with Symptoms of Gastroparesis.

Impaired fundic accommodation (FA) limits fundic relaxation and the ability to act as a reservoir for food. Assessing intragastric meal distribution (IMD) during gastric emptying scintigraphy (GES) allows for a simple measure of FA. The 3 goals of this study were to evaluate trained readers' (nuclear medicine and radiology physicians) visual assessments of FA from solid-meal GES; develop software to quantify GES IMD; and correlate symptoms of gastroparesis with IMD and gastric emptying. Methods: After training to achieve a consensus interpretation of GES FA, 4 readers interpreted FA in 148 GES studies from normal volunteers and patients. Mixture distribution and κ-agreement analyses were used to assess reader consistency and agreement of scoring of FA. Semiautomated software was used to quantify IMD (ratio of gastric counts in the proximal stomach to those in the total stomach) at 0, 1, 2, 3, and 4 h after ingestion of a meal. Receiver-operating-characteristic analysis was performed to optimize the diagnosis of abnormal IMD at 0 min (IMD0) with impaired FA. IMD0, GES, water load testing, and symptoms were then compared in 177 patients with symptoms of gastroparesis. Results: Reader pairwise weighted κ-values for the visual assessment of FA averaged 0.43 (moderate agreement) for normal FA versus impaired FA. Readers achieved 84.0% consensus and 85.8% reproducibility in assessing impaired FA. IMD0 based on the division of the stomach into proximal and distal halves averaged 0.809 (SD, 0.083) for normal FA and 0.447 (SD, 0.132) (P < 0.01) for impaired FA. On the basis of receiver-operating-characteristic analysis, the optimal cutoff for IMD0 discrimination of normal FA from impaired FA was 0.568 (sensitivity, 86.7%; specificity, 91.7%). Of 177 patients with symptoms of gastroparesis, 129 (72.9%) had delayed gastric emptying; 25 (14.1%) had abnormal IMD0 Low IMD0 (impaired FA) was associated with increased early satiety (P = 0.02). Conclusion: FA can be assessed visually during routine GES with moderate agreement and high reader consistency. Visual and quantitative assessments of FA during GES can yield additional information on gastric motility to help explain patients' symptoms.

Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis.

BACKGROUND: Idiopathic and diabetic gastroparesis in Homo sapiens cause significant morbidity. Etiology or risk factors have not been clearly identified. Failure to sustain elevated heme oxygenase-1 (HO1) expression is associated with delayed gastric emptying in diabetic mice and polymorphisms in the HO1 gene (HMOX1, NCBI Gene ID:3162) are associated with worse outcomes in other diseases. AIM: Our hypothesis was that longer polyGT alleles are more common in the HMOX1 genes of individuals with gastroparesis than in controls without upper gastrointestinal motility disorders. METHODS: Repeat length was determined in genomic DNA. Controls with diabetes (84 type 1, 84 type 2) and without diabetes (n = 170) were compared to diabetic gastroparetics (99 type 1, 72 type 2) and idiopathic gastroparetics (n = 234). Correlations of repeat lengths with clinical symptom sub-scores on the gastroparesis cardinal symptom index (GCSI) were done. Statistical analyses of short (<29), medium and long (>32) repeat alleles and differences in allele length were used to test for associations with gastroparesis. RESULTS: The distribution of allele lengths was different between groups (P = 0.016). Allele lengths were longest in type 2 diabetics with gastroparesis (29.18±0.35, mean ± SEM) and longer in gastroparetics compared to non-diabetic controls (28.50±0.14 vs 27.64±0.20 GT repeats/allele, P = 0.0008). Type 2 diabetic controls had longer alleles than non-diabetic controls. In all gastroparetic groups, allele lengths were longer in African Americans compared to other racial groups, differences in the proportion of African Americans in the groups accounted for the differences between gastroparetics and controls. Diabetic gastroparetics with 1 or 2 long alleles had worse GCSI nausea sub-scores (3.30±0.23) as compared to those with 0 long alleles (2.66±0.12), P = 0.022. CONCLUSIONS: Longer poly-GT repeats in the HMOX1 gene are more common in African Americans with gastroparesis. Nausea symptoms are worse in subjects with longer alleles.

Outcomes and Factors Associated With Reduced Symptoms in Patients With Gastroparesis.

BACKGROUND & AIMS: Gastroparesis is a chronic clinical syndrome characterized by delayed gastric emptying. However, little is known about patient outcomes or factors associated with reduction of symptoms. METHODS: We studied adult patients with gastroparesis (of diabetic or idiopathic type) enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium Gastroparesis Registry, seen every 16 weeks and treated according to the standard of care with prescribed medications or other therapies at 7 tertiary care centers. Characteristics associated with reduced symptoms, based on a decrease of 1 or more in the gastroparesis cardinal symptom index (GCSI) score after 48 weeks of care, were determined from logistic regression models. Data were collected from patients for up to 4 years (median, 2.1 y). RESULTS: Of 262 patients, 28% had reductions in GCSI scores of 1 or more at 48 weeks. However, there were no significant reductions in GCSI score from weeks 48 through 192. Factors independently associated with reduced symptoms at 48 weeks included male sex, age 50 years and older, initial infectious prodrome, antidepressant use, and 4-hour gastric retention greater than 20%. Factors associated with no reduction in symptoms included overweight or obesity, a history of smoking, use of pain modulators, moderate to severe abdominal pain, a severe gastroesophageal reflex, and moderate to severe depression. CONCLUSIONS: Over a median follow-up period of 2.1 years, 28% of patients treated for gastroparesis at centers of expertise had reductions in GCSI scores of 1 or greater, regardless of diabetes. These findings indicate the chronic nature of gastroparesis. We identified factors associated with reduced symptoms that might be used to guide treatment. ClinicalTrials.gov no: NCT00398801.

Clinical presentation and pathophysiology of gastroparesis.

Gastroparesis is a heterogeneous disorder defined by delay in gastric emptying. Symptoms of gastroparesis are nonspecific, including nausea, vomiting, early satiety, bloating, and/or abdominal pain. Normal gastric motor function and sensory function depend on a complex coordination between the enteric and central nervous system. This article discusses the pathophysiology of delayed gastric emptying and the symptoms of gastroparesis, including antropyloroduodenal dysmotility, impaired gastric accommodation, visceral hypersensitivity, and autonomic dysfunction. The underlying pathophysiology of gastroparesis is complex and multifactorial. The article discusses how a combination of these factors leads to symptoms of gastroparesis.

Pyloric sphincter therapy: botulinum toxin, stents, and pyloromyotomy.

Gastroparesis is a syndrome characterized by delayed gastric emptying with associated symptoms. Gastric emptying is a complex process and pyloric dysfunction may play a key role in select subsets of patients with gastroparesis. Diagnostic tests to measure pyloric physiology are now available and have the potential to be more widely used in clinical practice. Targeted therapies including botulinum toxin, transpyloric stent placement, surgical pyloroplasty and endoscopic pyloromyotomy have been developed. Data are emerging regarding efficacy and durability, but these therapies may play a prominent role in select patients with gastroparesis and pyloric dysfunction.

Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial.

IMPORTANCE: Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. Tricyclic antidepressants are often used to treat refractory symptoms of nausea, vomiting, and abdominal pain. Evidence from well-designed studies for this use is lacking. OBJECTIVE: To determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis. DESIGN, SETTING, AND PARTICIPANTS: The NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, a 15-week multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC), comparing nortriptyline with placebo for symptomatic relief in idiopathic gastroparesis. One hundred thirty patients with idiopathic gastroparesis were enrolled between March 2009 and June 2012 at 7 US academic medical centers. Patient follow-up was completed in October 2012. Inclusion criteria included delayed gastric emptying and moderate to severe symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI). INTERVENTIONS Nortriptyline vs placebo. Study drug dose was increased at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome measure of symptomatic improvement was a decrease from the patient's baseline GCSI score of at least 50% on 2 consecutive 3-week GCSI assessments during 15 weeks of treatment. RESULTS: The primary symptomatic improvement outcome did not differ between 65 patients randomized to nortriptyline vs 65 patients randomized to placebo: 15 (23% [95% CI, 14%-35%]) in the nortriptyline group vs 14 (21% [95% CI, 12%-34%]) in the placebo group (P = .86). Treatment was stopped more often in the nortriptyline group (19 [29% {95% CI, 19%-42%}]) than in the placebo group (6 [9%] {95% CI, 3%-19%}]) (P = .007), but numbers of adverse events were not different (27 [95% CI, 18-39] vs 28 [95% CI, 19-40]) (P = .89). CONCLUSIONS AND RELEVANCE: Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms. These findings do not support the use of nortriptyline for idiopathic gastroparesis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00765895.

Cholecystectomy and clinical presentations of gastroparesis.

BACKGROUND: Many patients with gastroparesis have had their gallbladders removed. AIM: To determine if clinical presentations of patients with gastroparesis differ in those with prior cholecystectomy compared to patients who have not had their gallbladder removed. METHODS: Gastroparetic patients were prospectively enrolled in the NIDDK Gastroparesis Registry. Detailed history and physical examinations were performed; patients filled out questionnaires including patient assessment of GI symptoms. RESULTS: Of 391 subjects with diabetic or idiopathic gastroparesis (IG), 142 (36 %) had a prior cholecystectomy at the time of enrollment. Patients with prior cholecystectomy were more often female, older, married, and overweight or obese. Cholecystectomy had been performed in 27/59 (46 %) of T2DM compared to 19/78 (24 %) T1DM and 96/254 IG (38 %) (p = 0.03). Patients with cholecystectomy had more comorbidities, particularly chronic fatigue syndrome, fibromyalgia, depression, and anxiety. Postcholecystectomy gastroparesis patients had increased health care utilization, and had a worse quality of life. Independent characteristics associated with prior cholecystectomy included insidious onset (OR = 2.06; p = 0.01), more comorbidities (OR = 1.26; p < 0.001), less severe gastric retention (OR(severe) = 0.68; overall p = 0.03) and more severe symptoms of retching (OR = 1.19; p = 0.02) and upper abdominal pain (OR = 1.21; p = 0.02), less severe constipation symptoms (OR = 0.84; p = 0.02), and not classified as having irritable bowel syndrome (OR = 0.51; p = 0.02). Etiology was not independently associated with a prior cholecystectomy. CONCLUSIONS: Symptom profiles in patients with and without cholecystectomy differ: postcholecystectomy gastroparesis patients had more severe upper abdominal pain and retching and less severe constipation. These data suggest that prior cholecystectomy is associated with selected manifestations of gastroparesis.