Gastroparesis is a chronic disorder characterized by delayed gastric emptying in the absence of mechanical obstruction, which results in typical symptoms of nausea, vomiting, bloating, abdominal distention, postprandial fullness, early satiation, and upper abdominal pain . Population-based studies have estimated the age-adjusted incidence rate of gastroparesis to be 2.4 patients per 100,000 person-years for men and 9.8 patients per 100,000 person-years for women, while prevalence was estimated to be 9.6 per 100,000 men and 37.8 patients per 100,000 females . However, these studies may be significantly underestimating the true prevalence of gastroparesis. One study reported 1.8% of the general population exhibited typical symptoms of gastroparesis but only 0.2% of patients were formally diagnosed . This may relate to lack of awareness of this condition, confusion about available methods for diagnosis of gastroparesis, and significant overlap between gastroparesis and related conditions, particularly functional dyspepsia.
Although the sine qua non of gastroparesis involves delayed gastric emptying, the pathophysiology of gastroparesis is heterogeneous and potentially involves several mechanisms ( Fig. 12.1 ) . By considering the pre-test probability for underlying pathogenic mechanism(s) associated with the predominant symptom complexes, this may help the clinician choose the most appropriate diagnostic test.
Impaired gastric accommodation
Upon meal ingestion, the gastric fundus undergoes a physiologic reflex called gastric accommodation mediated by nitrergic pathways, which results in increased volume of the gastric fundus without accompanying rise in intragastric pressure . Impaired gastric accommodation has been identified in up to 43% of patients with gastroparesis and correlated with symptoms of early satiation and weight loss .
Gastric neuromuscular dysfunction
Once the food bolus passes into the distal stomach, solid food is ground into small particles, in a process called trituration, by a combination of stomach acid and high-amplitude antral contractions . Antral contractions are mediated by extrinsic vagal innervation and intrinsic cholinergic neurons. Gastric emptying occurs when the food particles are 1–2 mm in size . Disruption in nitrergic neuronal pathways, including neuronal nitric oxide synthase (nNOS) immunoreactive cells in the gastric myenteric plexus , is postulated to be an important pathophysiologic mechanism in gastroparesis and may result in pyloric sphincter dysfunction or pylorospasm . As nitric oxide acts as an important survival factor the interstitial cells of Cajal , loss of these pacemaker cells in the gastrointestinal tract may result in antral hypomotility . These abnormalities in neuromuscular function may subsequently result in delayed gastric emptying.
Abdominal pain is a frequent symptom and reported by up to 90% of gastroparesis patients with up to 34% reporting severe or very severe pain . However, abdominal pain correlates poorly with gastric emptying of solids or liquids. Prior studies suggest abdominal pain may be related to visceral hypersensitivity to gastric distention . Patients with abdominal pain also demonstrated loss of S100 neural fibers in the gastric muscularis propria and altered central nervous system processing of pain signals .
Gastric emptying scintigraphy
Diagnosis of gastroparesis entails demonstrating objective evidence of delayed gastric emptying and exclusion of mechanical obstruction. Gastric emptying scintigraphy (GES) is the most common method for diagnosis of gastroparesis. Normative data with GES using a low-fat meal in healthy volunteers has been published with >60% retention of the test meal at 2 hours and >10% retention at 4 hours considered as abnormal .
GES has several advantages, including its wide availability, ability to measure emptying of both solid and liquid test meals as well as measures of gastric accommodation . However, despite consensus recommendations from the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine , the main limitation of GES remains the lack of standardization across different centers. There is also considerable intra-individual variation in gastric emptying rates with coefficients of variation of up to 24% . Furthermore, prior studies have reported poor correlation between gastric emptying rates and symptoms , which raises the question of whether gastric motility testing is required or even clinically useful for the diagnosis of gastroparesis . However, the latter two limitations are not unique to GES and apply to other tests of gastric transit as well, including wireless motility capsule.
Wireless motility capsule
Wireless motility capsule (SmartPill, Medtronic, Minneapolis, MN) is an ambulatory, ingestible capsule measuring 26.8×11.7 mm in size and houses sensors to record data on pH, temperature and pressure ( Fig. 12.2 ). This device is approved by the Food and Drug Administration (FDA) for evaluation of gastric emptying in patients with suspected gastroparesis as well as colonic transit testing in patients with chronic idiopathic constipation. In addition, the combined American and European Neurogastroenterology and Motility Societies recommended wireless motility capsule (WMC) as a validated test for assessment of gastric, small bowel, and colonic transit .
Test preparation and protocol
Patients are instructed to discontinue any medications (e.g. prokinetics, anticholinergics, laxatives, opioid analgesics) that may affect gastrointestinal motility at least 3 days prior to testing. Antisecretory agents may affect interpretation of the test and are also discontinued (proton pump inhibitors 7 days, histamine receptor antagonists 3 days prior, and antacids 1 day prior to testing). After an overnight fast, patients consume a standardized meal comprised of a nutrient bar (255 kcal which consists of 17% protein, 66% carbohydrate, 2.2% fat, and 3% fiber) and 50 mL of water. The WMC is then immediately ingested and a small data receiver is attached around the patient’s waist for the next 3–5 days which records data transmitted wirelessly from the device. Patients are instructed to avoid eating for 6 hours after the capsule is ingested while gastric emptying is measured. Afterwards, patients can resume their normal diets and daily activities. Patients are asked to record their meals, food intake, sleep, bowel movements, and symptoms during the test period.
WMC testing is contraindicated in patients with dysphagia to solid food or pills, swallowing disorders, and history of bezoars, strictures, or fistulae within the gastrointestinal tract. WMC is also contraindicated in patients with abdominal or pelvic surgery within the previous 3 months, and history of Crohn’s disease, diverticulitis, and/or surgery of the gastrointestinal tract. In patients with an implantable cardiac device, there are theoretical concerns that WMC may cause interference with a cardiac pacemaker or defibrillator from the capsule’s radio transmission of data. However, WMC is permitted in patients with gastric, bladder, or spinal stimulators and patients with insulin pumps. MRI examinations are not permitted for 7 days after WMC ingestion and capsule evacuation must be confirmed either by WMC tracing or by radiograph. Finally, WMC is only approved for adult patients ≥ 18 years old and is not indicated for use in the pediatric population.
WMC parameters in healthy individuals
WMC provides information pH and temperature throughout the gastrointestinal tract that can be used to calculate gastric emptying time (GET), small bowel transit time (SBTT), and colonic transit time (CTT) ( Fig. 12.3 ). GET is defined by the duration of time from capsule ingestion (evident by abrupt rise in temperature) until the capsule exits from the stomach which is marked by an abrupt rise in pH (usually ≥3 units) as the capsule passes from the acidic gastric environment to the more alkaline duodenum. The optimal cut-off time for GET was found to be ≤5 hours in order to discriminate between healthy subjects and gastroparesis patients . WMC showed a sensitivity of 0.65 and specificity of 0.87 for the diagnosis of gastroparesis which was similar to 4-hour GES (sensitivity 0.44, specificity 0.93).
SBTT is defined as the time from entrance of the WMC into the duodenum until its passage through the ileocecal value into the cecum, which is marked by a sustained drop in pH (usually >1 unit) . In cases where the drop in pH is not clear, abrupt changes in pressure wave frequency and/or amplitude may help define passage of the capsule into the cecum . CTT is defined as the time from capsule entry into the cecum until an abrupt drop in temperature and/or loss of recording signal indicating passage of the capsule from the body.
Normal values for SBTT and CTT was determined to be <6 hours and <59 hours, respectively . Wang et al. also evaluated regional gastrointestinal transit times using WMC in 215 healthy volunteers in the US and Sweden . These investigators reported a 95th percentile for SBTT and CTT to be 7:36 and 50:32, respectively. These results suggest establishing a longer small bowel transit time and shorter colonic transit time for normal values compared to previous data while transit times may vary based on age, gender, and location. However, Wang and colleagues utilized two different study protocols which differed in the composition and timing of the test meal utilized, which may have influenced gastrointestinal transit time.
In a study of 10 healthy volunteers, Maqbool et al. compared whole gut transit parameters as measured by WMC with whole gut scintigraphy . These authors noted a strong correlation in GET by WMC and gastric retention by scintigraphy ( r= 0.95, P <.01). They also reported moderate correlation in small bowel contraction/min by WMC and small bowel transit by scintigraphy (r=0.69, P =.05) as well as whole gut transit by WMC and scintigraphy ( r= 0.5, P =.09).
Transit times as measured by WMC have also been shown to be reproducible. Intra-subject variability in pH and transit times were measured in 10 healthy volunteers who ingested two WMC 24 hours apart . These authors found that the mean intra-subject coefficient of variation (COV) for small bowel and colonic transit times were 12.0±7.4% and 25.8±15.8%, respectively ( P =.01). These results suggest that the reproducibility of transit testing by WMC is comparable or superior to scintigraphy (COV 19% for SBTT, 14–28% for CTT) or lactulose hydrogen breath test (COV 18.5 – 29.7% depending on dose of lactulose given) . They also noted that the pH profile throughout the gut does not fluctuate markedly in a given region (median intra-subject variability in pH 0.05 throughout the gut). However, one notable weakness of this study is the lack of reporting on the reproducibility of GET.
An innovative feature of WMC is its ability to measure intraluminal pressure profiles throughout the gastrointestinal tract, including the number of contractions per minute, the maximum amplitude of contractions, and mean peak amplitude of contractions. This information can be utilized to determine a motility index (MI), which is calculated by taking the natural log of the sum of the pressure amplitudes of all contractions multiplied by the number of contractions + 1, as well as the area under the curve (AUC), which is the total area under the curve for the window chosen .
Normative values for the number of contractions (Ct), AUC, and MI have been published. In a post-hoc analysis, Kloetzer et al. evaluated pressure profiles assessed by WMC in 71 healthy subjects and 42 patients with confirmed gastroparesis . The fifth percentile of healthy subjects had ≤29 Ct/hour in the stomach, defined as the 1-hour window prior to GET, and ≤36 Ct/hour in the duodenum, defined as the 1-hour window after GET. The fifth percentile values for gastric and duodenal MI were ≤9.82 and ≤10.57, respectively, while gastric and duodenal AUC values were ≤1358 mm Hg/s and ≤1456 mm Hg/s, respectively.
Farmer et al. also described normative values for motility parameters using WMC in 107 healthy individuals . These authors found fifth percentile of healthy subjects had gastric and duodenal Ct of 24/hour and 90/hour, respectively. The fifth percentile values for gastric and small bowel MI were 11.3 and 13.9, respectively, while gastric and small bowel AUC were 1544 mm Hg/s and 7529 mm Hg/s, respectively. Given the discrepancy between these two studies, these data suggest that there may be a wide variation in normative values for contractile parameters obtained by WMC. Furthermore, unlike antroduodenal manometry, WMC is a freely moving non-tethered device containing only a single pressure sensor which precludes assessment of organized contractile patterns, such as the migrating motor complex or propagation of peristaltic waves. These results along with the transit data highlight the need to establish consensus criteria for normative transit and pressure data.
Performance characteristics in gastroparesis
Kuo et al. published an industry sponsored multicenter trial comparing gastric emptying time (GET) as measured by WMC with gastric emptying scintigraphy (GES) . Eighty-seven healthy subjects and 61 patients with documented delayed gastric emptying within the past 2 years underwent simultaneous WMC and GES. There was moderate correlation between gastric emptying time by WMC and meal retention (%) at 2 hours ( r= 0.63) and 4 hours by GES ( r= 0.73). WMC also showed similar accuracy in differentiating between patients with delayed and normal gastric emptying (area under the receiver operator characteristic curve, AUC=0.83) compared with GES-2 h and GES-4h (AUC=0.79, 0.82, respectively).
In the largest study to date, the NIH-sponsored Gastroparesis Consortium prospectively enrolled 209 patients with suspected gastroparesis and compared gastric emptying by WMC and GES . In this study, Hasler and colleagues reported delayed solid and liquid GES in 68.8% and 34.8% of patients, respectively, while delayed GET by WMC was noted in 40.3%. WMC showed a much lower rate of device agreement with scintigraphy (kappa=0.12) compared with the initial report by Kuo et al. . These authors also noted diabetic patients were more likely to have delayed GET by WMC compared to patients with idiopathic gastroparesis (51.5% vs. 32.8%, P =.01). No associations were noted between gastroparesis symptoms and severity of gastric emptying delays by GES or WMC.
Recently, Lee et al. published the results from an industry sponsored multicenter, comparative, prospective cohort study, which compared the performance characteristics of WMC and GES in 167 patients with suspected gastroparesis from 10 academic and community centers across the US . WMC and GES showed a moderate level of agreement with overall device agreement noted in 75.7% (kappa=0.42). Furthermore, WMC showed higher diagnostic yield for detecting delayed gastric emptying compared with GES (34.6% vs 24.5%, P =.009) ( Fig. 12.4 ). There were also differences by subgroup analyses. In particular, non-diabetic patients, which comprised approximately 2/3rd of the population, were more likely to have delayed gastric emptying detected by WMC compared with GES (33.3% vs. 17.1%, P <.001). In contrast, diabetic subjects were more likely to have delayed gastric emptying by GES compared with non-diabetic subjects (41.7% vs. 17.1%, P =.002).
It may be informative to describe differences in patient populations and methodologies between these three studies to provide context and help interpret the results. First, both studies by Kuo and Hasler and colleagues were heavily enriched with patients who had previously been diagnosed with gastroparesis. In contrast, the study by Lee et al. enrolled patients with suspected gastroparesis but no previous formal diagnosis. Indeed, the majority of patients ultimately had normal gastric emptying by GES and WMC. This scenario is more reflective of clinical reality where dyspeptic symptoms do not reliably distinguish between patients with normal vs. delayed gastric emptying . Secondly, in the study by Hasler et al., GES was always performed first followed sequentially by WMC up to 6 months later whereas GES and WMC were performed simultaneously in the other two studies. Prior studies have documented a significant intra-individual variation in gastric emptying rates of up to 24% which may partially explain the discrepancy in device agreement between these studies . Furthermore, data from the Gastroparesis Consortium suggests that gastric emptying is more likely to normalize in patients with idiopathic gastroparesis compared with diabetic patients . As GES was always performed first in this study by Hasler et al., it is possible that gastric emptying had normalized by the time WMC was performed which may have influenced the rate of device agreement. Finally, the patient cohort enrolled in the Gastroparesis Consortium likely represents a severe phenotype of gastroparesis with 15% of diabetic patients undergoing placement of a gastric electrical stimulator and more than 10% requiring nutritional support . For these reasons, the study by Lee and colleagues are more reflective of real-world scenarios and these results may be more generalizable to most clinicians.
Small bowel transit
As patients with gastroparesis often have overlapping upper and lower gastrointestinal symptoms , one of the potential advantages of WMC is its ability to obtain extra-gastric transit information. Few studies have evaluated small bowel transit time in gastroparesis. In an industry-sponsored trial of 66 healthy controls and 34 patients with gastroparesis, there were no differences in small bowel transit times in patients with gastroparesis compared with healthy controls . Retrospective studies have demonstrated abnormal small bowel transit in 5–15% of patients with suspected gastrointestinal dysmotility . In prospective studies, WMC detected delayed small bowel transit times in 15.5% of patients with documented gastroparesis . Meanwhile, 22.8% of patients with suspected gastroparesis had delayed small bowel transit, particularly in non-diabetic patients where small bowel transit was delayed in 26.6% . It is important to note that small bowel transit times cannot be determined in 5–10% of patients in clinical trials due to inability to identify the characteristic drop in pH associated with passage of the capsule through the ileocecal valve .
Although the clinical significance of delayed small bowel transit in gastroparesis is unknown, one study demonstrated irritable bowel syndrome (IBS) patients with concomitant delayed gastric emptying by scintigraphy were more likely to have small bowel abnormalities by antroduodenal manometry compared with IBS patients with normal gastric emptying . Studies in patients with confirmed delayed GES showed 39–60% were positive for small intestinal bacterial overgrowth (SIBO) by breath testing . Moreover, in a retrospective study of 37 patients who underwent both WMC and lactulose breath test, patients who were positive for SIBO by breath testing demonstrated longer small bowel transit time compared with those negative for SIBO (6.6 h vs. 4.2 h, P =.04) . Patients positive for SIBO by breath tests also had higher rates of delayed small bowel transit time compared with SIBO-negative patients (47.6% vs. 7.7%, P =.01). These results suggest that small bowel transit delays may be an under-recognized cause of symptoms in gastroparesis.
Patients with gastroparesis may also have co-existing colonic dysmotility which may affect symptom burden. In a retrospective analysis of 206 patients with chronic dyspeptic symptoms and constipation who underwent GES, there was a significantly higher rate of slow transit constipation by radiopaque marker (ROM) testing in patients with delayed vs. normal gastric emptying by scintigraphy (64.7% vs. 28.1%, P =.01) . In prospective studies, delayed CTT was noted in 33.5% of patients with history of gastroparesis and 31.5% of patients with suspected gastroparesis . Notably, the prevalence of slow transit constipation in patients presenting with primary complaints of constipation ranges from 38 to 80% depending on the method of testing . Compared with 41 healthy controls and 8 diabetic subjects with normal gastric emptying, 12 patients with diabetic gastroparesis demonstrated slower colonic transit times and reduced colon contractions, which were significantly blunted, particularly in the latter phases of colonic transit . These results emphasize that patients with gastroparesis have significant overlap between upper and lower gastrointestinal symptoms and suggest a more generalized gut dysmotility in a subset of gastroparesis patients.
Colon transit time (CTT) as measured by WMC has been compared with ROM testing in an industry sponsored multi-center trial of 78 patients with Rome II functional constipation and 87 healthy individuals . These authors found that CTT by WMC showed good correlation with the number of retained ROMs on day 2 and day 5 in functional constipation ( r =0.74 and 0.69, respectively) and in healthy patients ( r =0.70 and 0.40, respectively) with an overall correlation of 0.78 and 0.59, respectively. A follow-up multi-center study of 158 patients meeting Rome III criteria for chronic functional constipation compared CTT by WMC with ROM testing . WMC showed a significant correlation with ROM markers for measuring CTT ( r =0.707, P <.001) and combined small and large bowel transit time ( r =0.704, P <.001). The overall device agreement between WMC and ROM testing was 87%. However, CTT as measured by ROMs was significantly longer compared with WMC (median 55.0 h vs 43.5 h, respectively, P <.001). These differences in CTT likely reflect differences in particle sizes between ROM and WMC which influences transit times in the small bowel and colon . Nevertheless, WMC is approved by the FDA for evaluation of colonic transit time in patients with chronic idiopathic constipation.
Upper gastrointestinal pressure parameters
Prior studies have demonstrated that delayed gastric emptying is correlated with antral hypomotility and intestinal dysmotility . However, evaluating for hypomotility traditionally required use of antroduodenal manometry, which is invasive and rarely performed in clinical practice today. To compare pressure patterns within the antrum and duodenum, WMC and antroduodenal manometry were performed simultaneously in 15 healthy volunteers . In 9/14 (64%) of patients, gastric emptying of WMC occurred with return of phase III of the migrating motor complex indicating return of the fasting motor state. Gastric emptying time for the WMC was strongly correlated with the time for return of the first phase III migrating motor complex after a meal ( r =0.813, P <.01). In the remaining 5 patients, gastric emptying of WMC occurred with high amplitude antral contractions. Furthermore, pressure tracings measured by WMC resembled those recorded by more traditional antroduodenal manometry. While WMC cannot detect peristaltic wave propagation, these results suggest motility parameters obtained by WMC may be a useful surrogate to more invasive techniques, such as antroduodenal manometry.
In a post-hoc analysis, Kloetzner et al. demonstrated significant differences in antroduodenal pressure patterns as measured by WMC in 42 patients with confirmed diagnoses of gastroparesis compared with 71 healthy controls . Patients with gastroparesis showed significantly reduced number of contractions (Ct) and motility index (MI) in the stomach (Ct 47 vs. 72 per hour, P =.01; MI 11.12 vs. 11.83, P =.02, respectively) and small bowel (Ct 93 vs. 145 per hour, P =.02; MI 12.12 vs. 12.78, P =.04) compared with healthy subjects. Overall, 33% of gastroparesis patients had gastric Ct frequencies below the 5th percentile for healthy subjects while this rate increased to 52% in patients with GET >5 h and 73% if GET was severely delayed (>12 h). Patients with diabetic gastroparesis showed significantly lower Ct and MI in the stomach and duodenum whereas there were no differences in motility parameters between idiopathic gastroparesis and healthy controls.
Lee et al. evaluated the prevalence of transit and antroduodenal pressure abnormalities in a post-hoc analysis of 43 gastroparetic patients undergoing simultaneous WMC and GES . These authors found that 41% of patients had evidence of delayed gastric emptying by GES. In comparison, 60% of subjects had delayed GET while 47% had abnormal gastroduodenal pressure profiles measured by WMC. Overall, WMC led to a diagnostic gain of 19% ( P =.04) compared with GES. These results provide support that antroduodenal pressure parameters measured by WMC may provide an additional diagnostic advantage compared with tests solely investigating gastric emptying.
As postprandial symptoms are common in gastroparesis patients, Surjanhata et al. performed a post-hoc analysis of two studies to determine whether gastroparesis patients may have abnormal postprandial gastroduodenal motor patterns . Compared with 107 healthy subjects and 58 patients meeting Rome II criteria for chronic functional constipation, 23 patients with an established diagnosis of gastroparesis demonstrated reduced small intestinal motility parameters as measured by WMC in the 60-minute period after ingestion of a liquid meal relative to baseline measurements. While healthy controls and patients with chronic functional constipation demonstrated an increase in mean postprandial Ct compared with baseline that peaks at 40 minutes after meal ingestion and then decreases by 60 minutes, patients with gastroparesis exhibited a blunted motor pattern after meal ingestion. This suggests that gastroparesis patients may have an impaired small bowel fed motor response which can be captured non-invasively by WMC.
Clinical utility of monitoring transit and pressure parameters in gastroparesis
Due to the poor correlation between gastric motility tests and symptoms, the clinical utility of performing motility testing has come under considerable doubt recently. However, recent studies have suggested that delayed gastric emptying was associated with worse symptom scores. A systematic review and meta-analysis from 92 studies identified 25 studies with quantitative data available to assess the relationship between gastric emptying and upper GI symptoms . Meta-regression demonstrated significant differences between upper GI symptoms and gastric emptying tests when performed with optimal and suboptimal methodology ( Fig. 12.5 ). Furthermore, when only studies with optimal test methodology were included, there were significant associations between delayed gastric emptying and increased odds for symptoms, including nausea (OR 1.6, 95% CI 1.4–1.8), vomiting (OR 2.0, 95% CI 1.6–2.7), abdominal pain (OR 1.5, 95% CI 1.0–2.2) and early satiety/fullness (OR 1.8, 95% CI 1.2–2.6).