Introduction

The NIH Gastroparesis Clinical Research Consortium (GpCRC) was started in 2005 to improve the understanding of the pathogenesis and natural history of gastroparesis of all etiologies and to advance the diagnosis and therapy of patients affected with this troubling condition. The consortium initially consisted of five centers along with the data coordinating center and the NIH. Over the initial 13 years of study from a number of centers of excellence in gastroparesis, the GpCRC has learned a tremendous amount about gastroparesis as well as conditions with symptoms of gastroparesis but with normal gastric emptying. The areas of study can be divided into five important areas: symptoms, etiologies, pathophysiology, physiologic testing, and treatments. This chapter briefly summaries some of the findings of the Gastroparesis Clinical Research Consortium as published in peer reviewed manuscripts.

Symptoms

The clinical burden of gastroparesis for patients with this disorder is high. Symptoms can be severe and continuous or with variations in severity over time. Different patients may have different types of predominant symptoms, such as nausea/vomiting or early satiety/postprandial fullness. In the GpCRC studies, symptoms of gastroparesis have been quantified using a modified Patient Assessment of Upper Gastrointestinal Disorders Symptoms (PAGI-SYM) questionnaire which assesses symptoms of gastroparesis, dyspepsia, and gastroesophageal reflux disease ; it includes the nine symptoms of the Gastroparesis Cardinal Symptom Index (GCSI) . This modified PAGI-SYM includes additional individual symptom scores for lower abdominal pain, constipation and diarrhea to help assess these lower GI symptoms.

Nausea appears to be the primary symptom as it is present in nearly all patients (95%) . Nausea and vomiting, in particular, are related to the decreased quality of life these patients have. Vomiting is less prevalent than nausea. Vomiting is more prevalent and severe in diabetic gastroparesis than idiopathic gastroparesis. Early satiety and postprandial fullness are also important symptoms . The severity of early satiety and postprandial fullness is associated with body weight, quality of life, and gastric emptying.

Abdominal pain has largely been ignored in gastroparesis; its cause is unknown. Abdominal pain is reported to be the predominant symptom in one-fifth of patients with gastroparesis . Moderate-severe abdominal pain is present in 66% of patients with gastroparesis, impairs quality of life, and is associated with idiopathic etiology and opiate use, but not gastric emptying. Patients with predominant pain have at least as great an impact on disease severity and quality of life as in patients with predominant nausea/vomiting. Increased upper abdominal pain severity was associated with increased severity of each of the nine GCSI symptoms, depression, anxiety, somatization, use of opiate medications, decreased quality of life using the two instruments used by the GpCRC, the generic QOL instrument SF-36 and the more disease specific QOL instrument PAGI-QOL, but not related to severity of delayed gastric emptying or water load ingestion .

Many patients with gastroparesis use opioids for pain control. In the GpCRC registry, 41% of 583 gastroparesis patients were taking opioids . 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. 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. Thus, in the clinic, 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. Opiates, although might be helpful for acute traumatic or postsurgical pain, are now not suggested for long term use. In addition, opiates can not only delay gastric emptying, but can cause GI symptoms such as nausea and vomiting. Most treatment trials in gastroparesis limit the use of opiates for study subjects. In the current environment of limiting use of opiates due to their side effects, the number of gastroparesis patients taking opiates will hopefully decrease.

In addition to gastric symptoms, many patients with gastroparesis and the wider population of patients with symptoms of gastroparesis with or without delayed gastric emptying can have symptoms of anxiety and depression . The severity of these symptoms relates to the severity of the gastroparesis symptoms. Psychological dysfunction does not vary by etiology or degree of gastric retention. Although it is likely that the chronic gastric symptoms, which may persist despite treatments, may lead to anxiety and depression, it is interesting to speculate that these central symptoms may themselves be impacting on the gastric-related symptoms. The vagus nerve has bidirectional neural pathways, with efferent motor pathways to the stomach as well as afferent sensory pathways to the CNS. Psychological symptoms should be considered in managing gastroparesis, and often they need to be treated.

Etiologies

The NIH GpCRC has studied primarily idiopathic and diabetic gastroparesis. The second registry also contained patients with postsurgical gastroparesis, specifically post Nissen fundoplication gastroparesis.

The clinical features of idiopathic gastroparesis were described in 243 patients in the first NIH GpCRC gastroparesis registry (GpR1) . The mean age of the patients with idiopathic gastroparesis was 41 years with 88% being female and surprisingly 46% being overweight or obese. The onset of symptoms revealed that 50% had an acute onset of symptoms with 19% reported an initial infectious prodrome. Predominant presenting symptoms included nausea (34%), vomiting (19%), and abdominal pain (23%). Severely delayed gastric emptying was associated with worse vomiting, loss of appetite, and overall gastroparesis symptoms. 86% of patients with idiopathic gastroparesis met criteria for functional dyspepsia (Rome III definition at the time of GpR1), especially postprandial distress syndrome. This is not surprising as dyspepsia is a symptom based disorder based on gastric dysfunction. Thus, idiopathic gastroparesis is a diverse syndrome; varies by sex, body mass, symptom onset, gastric emptying. It primarily affects young women, beginning acutely in 50% of cases; unexpectedly, many patients are overweight. Severe delay in gastric emptying was associated with vomiting and loss of appetite.

Diabetic gastroparesis is the classic disorder of gastroparesis, being present in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Patients with diabetic and idiopathic gastroparesis were compared . Symptoms prompting evaluation were often vomiting for diabetic gastroparesis and abdominal pain for idiopathic gastroparesis. Diabetic gastroparesis had more severe retching and vomiting than those with idiopathic, whereas idiopathic gastroparesis had more severe early satiety and postprandial fullness subscores. Gastric retention was greater in patients with type 1 DM with more than 50% of patients with type 1 DM had severe retention (>35% at 4 hours). T1DM took prokinetic agents more frequently, had more hospitalizations, and were more likely to receive gastric electric stimulation therapy. Thus, there are similarities and differences in clinical characteristics of diabetic and idiopathic gastroparesis. Gastroparesis is a heterogeneous disorder with the etiology affecting symptoms and severity.

There is limited information on gastroparesis in minority populations. Ethnic, racial, and sex differences appear to affect etiologies, symptom severity, and treatments in patients with gastroparesis . A higher proportion of blacks (60%) had gastroparesis of diabetic etiology than of whites (28%); blacks also had more severe retching and vomiting and a higher percentage were hospitalized in the past year (66% vs 38%). There was also a higher proportion of Hispanics who had gastroparesis of diabetic etiology (59%) than non-Hispanic whites (28%), but Hispanics had less-severe nausea, less early satiety, and a lower proportion used domperidone (8% vs 21%) or had a peripherally inserted central catheter (1% vs 7%). Women had higher proportion with gastroparesis of idiopathic etiology (69%) than men (46%) with women having more severe symptoms of stomach fullness, early satiety, postprandial fullness, bloating, stomach visibly larger, and upper abdominal pain.

GpR1 enrolled patients with symptoms of gastroparesis, allowing a fraction (25%) to have normal gastric emptying. The GpCRC has termed the condition of symptoms of gastroparesis but with normal gastric emptying, Chronic Unexplained Nausea/Vomiting (CUNV), as nearly all have nausea and vomiting as symptoms . In a study of 425 patients with chronic nausea and vomiting; 319 (75%) had delayed, but 106 normal gastric emptying. The patients with normal gastric emptying had similar symptom severity for nausea, retching, vomiting, stomach fullness, early satiety, postprandial fullness, loss of appetite, bloating. Total GCSI was not correlated with gastric retention. Those with delayed gastric emptying were more likely to be diabetic. State anxiety scores were slightly higher among patients with delayed gastric emptying. Thus, patients with chronic nausea and vomiting with normal gastric emptying are, for the most part, indistinguishable from those with gastroparesis. It may be appropriate to reconsider the definition of gastroparesis, recognizing it as a broader spectrum of gastric neuromuscular dysfunction .

Pathophysiology

The GpCRC defined gastroparesis using gastric emptying scintigraphy using the EggBeater sandwich with jam and water meal with 4 hour postprandial imaging . Imaging occurred at 0, 1, 2, 4 hours after meal ingestion. This protocol ensures standardized information about gastric emptying across sites. Abnormal values defining gastroparesis included 2 hour retention >60% and/or 4 hour retention >10%.

During gastric emptying, the initial process involves fundic accommodation to allow entry of the meal into the stomach followed by antral peristaltic contractions with coordinated pyloric sphincter relaxation (opening), allowing entry of triturated food into the duodenum. Impaired fundic accommodation (FA) limits fundic relaxation and the ability to act as a reservoir for food resulting in rapid progression of the ingested meal from the fundus to the antrum. Assessing intragastric meal distribution (IMD) during gastric emptying scintigraphy (GES) may provide additional information on gastric motility. Intragastric meal distribution (IMD) was studied during gastric emptying scintigraphy . IMD ⁰ (the IMD at time zero after meal ingestion) was based on division of stomach into proximal and distal halves. IMD values averaged 0.809 for patients with normal fundic accommodation (FA), as judged visually scintigraphically and 0.447 ( P <.01) for patients with impaired FA. Optimal cutoff for IMD ⁰ discrimination of normal FA from impaired FA was 0.568 with sensitivity of 87% and specificity of 92%. Of 177 patients with symptoms of gastroparesis, 129 (73%) had delayed gastric emptying; 25 (14%) had abnormal IMD ⁰ . Low IMD ⁰ (<0.568; impaired FA) was associated with increased early satiety ( P =.02). Thus, visual and quantitative assessments of IMD can yield information on gastric motility to help explain patients’ symptoms.

The wireless motility capsule (WMC) records pH, pressure, temperature as the ingested capsule traverses through the GI tract. The WMC can be used to assess gastric emptying as well as small bowel and colonic transit. In GpR2, patients underwent gastric emptying scintigraphy and wireless motility capsule studies, albeit at different times. The WMC defined gastric emptying delays similar but not identical to scintigraphy which were more severe in diabetics and relate to reduced gastric contractility . Extragastric transit delays occurred in about 40% with suspected gastroparesis. Constipation correlated with slower colonic transit time and higher colon contractions.

Diabetic gastroparesis often occurs in patients with other complications of diabetes, such as peripheral neuropathy, nephropathy, and retinopathy (often term “triopathies”). Diabetic gastroparesis is often considered a neuropathy of the vagus nerve. The relationships of these complications were explored in relation to their association with delayed gastric emptying . In diabetic patients with symptoms of gastroparesis, delayed gastric emptying was associated with presence of retinopathy and total number of diabetic complications. Although no differences were noted in the proportion of patients with diabetic complications, the number of triopathies was greater in T1DM compared to T2DM. Presence of diabetic complications should raise awareness for pursuing gastroparesis in either T1DM or T2DM. However, it should be noted that diabetic gastroparesis can still occur without other diabetic complications.

Gastroparesis can reflect abnormalities of the nervous system on a larger scale. Autonomic function and abnormalities were studied in 242 patients with symptoms of gastroparesis (patients with gastroparesis and CUNV) . Autonomic function testing was performed using ANSAR ANX 3.0 autonomic monitoring system which measures sympathetic (S) and parasympathetic (P) function at rest and following challenges to the ANS, which include Valsalva (S), deep breathing (P), and standing (P & S). Autonomic dysfunction was common in patients with gastroparesis or CUNV, with diabetics presenting with greater global dysfunction. Parasympathetic hypofunction was associated with delayed gastric emptying and more severe upper gastrointestinal symptoms. Conversely, sympathetic hypofunction was associated with milder symptoms.

A major benefit of the GpCRC was its ability to collect full thickness gastric biopsy specimens at the centers of excellence, where medically refractory patients were undergoing implantation of the gastric electric stimulator to try to help improve symptoms. This tissue repository allowed enteric pathology in gastroparesis to be extensively studied . The most common findings in patients with gastroparesis from full thickness biopsies are: (1) loss of c-Kit expression suggesting loss of interstitial cells of Cajal; (2) increase CD45 immunoreactivity suggesting increase of inflammatory cells; and (3) loss of nNOS (neuronal loss rarely seen, suggesting that there is no neuronal “burn-out”). Interestingly, the number of CD206-positive M2 macrophages correlated with the number of ICC, suggesting CD206-positive macrophages may play cytoprotective role in diabetes . These findings suggest examination of tissue can lead to valuable insights into the pathophysiology and offer hope that new therapeutic targets can be found. In mice studies, loss of anti-inflammatory HO1-positive/CD206-positive M2 macrophages and an increase of proinflammatory M1 macrophages are associated with the development of delayed gastric emptying. Interleukin-10 was shown to restore gastric emptying, electrical activity, and interstitial cells of Cajal networks in diabetic gastroparetic mice.

Treatments

Treatments for gastroparesis often involve dietary management, prokinetic agents, and antiemetic agents. Patients not responding to these measures can be considered for surgical treatments, which now may include gastric electric stimulation and/or pyloromyotomy.

Patients in GpR1, once enrolled, were followed over several years with follow up visits every 3 months. During this time, their gastroparesis were treated by their physicians, often by the investigators at the centers of excellence as best they could. The outcomes of the patients with gastroparesis in NIH GpR1 were evaluated . Of patients with gastroparesis (diabetic or idiopathic) in GpR1, only 28% of 262 patients symptomatically improved at 48 weeks with decrease GCSI ≥1. This improvement of ≥1 in the GCSI is analogous to a decrease in symptoms from severe to moderate or from moderate to mild, and thought to represent important clinical improvements for patients. The low number of patients improving over time illustrates the chronic nature of gastroparesis and that the disease burden of gastroparesis remains high. Factors related to clinical improvement included: age ≥50 years, elevated GCSI score, use of antidepressants, gastric retention >20% at 4 hours, an initial infectious prodrome. Negative factors for improvement included use of anxiolytics, use of pain modulators, presence of moderate/severe abdominal pain, being overweight/obese, depression, smoking history, and gastroesophageal reflux severity.

Dietary factors of patients are an important area in the care of patients with gastroparesis. The gastroparesis disorder can limit the amount of food that patients can ingest. In addition, dietary management often is used for treatment of gastroparesis. Dietary intake and nutritional deficiencies were determined in 305 patients with gastroparesis on oral intake using the Block Food Frequency Questionnaire to determine nutritional consumption . Overall, caloric intake averaged only 1168 kcal/day, representing 58% of daily total energy requirements (TER). 194 patients (64%) reported caloric-deficient diets, defined as <60% of estimated TER. Surprisingly, only 5 patients (2%) followed a diet suggested for patients with gastroparesis. Deficiencies were present in several vitamins and minerals. Only a third of patients were taking multivitamin supplements. More severe symptoms (bloating and constipation) were present in those consuming an energy-deficient diet. Surprisingly, only 32% of patients had nutritional consultation after the onset of gastroparesis. Nutritional consultation increased chances daily TER were met (odds ratio, 1.51; P =.08). Thus, many patients with gastroparesis have diets deficient in calories, vitamins, and minerals. Nutritional consultation is suggested for dietary therapy and to address nutritional deficiencies.

One of the initial treatment studies of the GpCRC was addressing diabetic control in patients with diabetic gastroparesis. At the time of the study, many diabetic patients with gastroparesis were kept at slightly elevated glucose levels due to the concern the glucose might fall to hypoglycemic values if good tight control was sought. Many diabetic gastroparesis patients were kept “out of control”. Continuous glucose monitoring (CGM) together with insulin pump therapy in diabetic gastroparesis (GLUMIT-DG) was studied in 45 diabetic gastroparesis patients who were poorly controlled with HgbA1c>8%. The patients had 21±11 years of diabetes duration with 29% being type 1 DM. Patients were treated with intensive insulin regimens using insulin pumps with continuous glucose monitoring (CGM). During this six month study, the baseline A1c levels (9.4±1.4%) decreased by 1.1% at 24 weeks ( P =.0002). This study showed that good glucose can be obtained in patients with diabetic gastroparesis with minimal change in the hypoglycemic events. In addition to improved glucose control, patients in the study had reduction in symptoms and improvement in nutrient tolerance benefits which were maintained for 24 weeks of therapy. The main outcome was that this study showed feasibility for improving both diabetes control and lowering gastroparesis symptoms.

Symptom modulators are used to reduce symptoms without addressing the delayed gastric emptying, as is done with the use of prokinetic agents which act to improve the delayed gastric emptying. The GpCRC nortriptyline study for patients with idiopathic gastroparesis (NORIG Trial) showed that nortriptyline treatment did not improve overall symptoms, as defined by the primary outcome measure (GCSI total score), in idiopathic gastroparesis over a 15 week period. There were some interesting findings though with this study. After the initial 3 weeks of treatment, there was improvement in nausea and abdominal pain at the initial low dose of nortriptyline (10 mg), but not sustained over time as dosing was increased. At 15 weeks of treatment, higher doses of nortriptyline were associated with improvements in appetite, satiety, and body weight.

Nausea and vomiting in gastroparesis is often treated with the 5-HT3 receptor antagonists. During the first five year cycle, the neurokinin pathway was being used to treat chemotherapy induced nausea and vomiting using NK-1 receptor antagonists. This pathway might be involved in the nausea and vomiting seen in patients with gastroparesis and CUNV. The randomized multicenter, double-masked 4-week trial of the neurokinin-1 receptor antagonist aprepitant (Emend) was performed to see if aprepitant reduced symptoms of chronic nausea and vomiting in patients with gastroparesis or gastroparesis-like syndrome (symptoms of gastroparesis but normal gastric emptying) . In this double blind study, aprepitant 125 mg daily reduced nausea and other symptoms in patients with symptoms of gastroparesis (both delayed and normal gastric emptying). The positive result in nausea was seen in the GCSI, a secondary measure used in this study, but not using the primary outcome measure, a nausea visual analog scale.

Gastric electrical stimulation in gastroparesis was studied in a pragmatic open label study of patients in the first gastroparesis registry . The results from the prospectively collected database of GpR showed that 92 (14.5%) of patients initiated gastric stimulation (GES) after GpR enrollment; 48-week data from GES patients compared 542 no GES pts (control group). 38% of patients with GES were diabetic and 54% idiopathic. Patients who underwent GES had more delayed gastric emptying at 4 hrs (30.9 vs 21.8%) with worse GCSI scores (3.8 vs 3.0) at enrollment before stimulator placement. After 48 weeks, GCSI scores in patients with GES improved by average of 0.9 compared with 0.3 in controls (p<0.001) with 43.6% showing improvement of at least 1 point compared with only 24.7% in controls ( P =.004). In this observational study in multiple practice settings, 15% of gastroparesis required GES therapy. Patients with more severe overall symptoms were more likely to improve symptomatically, primarily for nausea.

In today’s environment, the orexigenic, antinauseant and pain-relieving properties of marijuana attract many patients with chronic nausea and vomiting symptoms such as in gastroparesis. Marijuana use in patients with symptoms of gastroparesis was studied in a pragmatic research study design . 59 of 505 (11.7%) patients with symptoms of gastroparesis reported use of marijuana. Use was similar among patients with delayed and normal gastric emptying and in idiopathic and diabetics. Marijuana users had higher nausea/vomiting (2.68 vs 2.08), higher upper abdominal pain (3.50 vs 2.88). The higher severity of symptoms in the patients using marijuana were interpreted as the higher symptomatic score leading to the use of marijuana for treatment, although the data could be interpreted as the marijuana use might have led to the increase in symptom severity. Most patients using marijuana had chronic symptoms (80%); a minority having cyclic symptoms (20%). Marijuana uses, 51% had been using this for more than 2 years, 47% of patients using this once or more per day, and 81% of patients rated their benefit from marijuana as better or much better. Comparatively 4.4% were using dronabinol. 55% using dronabinol for 1–6 months, with 77% rating their benefit as better or much better. Marijuana users had increased anxiety, panic indices which have been reported in other studies of marijuana users. Thus, a significant minority (12%) of patients with symptoms of gastroparesis use marijuana. Patients with severe nausea and abdominal pain more likely to use marijuana, consistent with its perceived benefits. The synthetic analog, dronabinol, used by small minority, comparable in efficacy to marijuana. Physicians should inquire about use of marijuana and other cannabinoids in their patients.

Conclusions

The studies from The NIH Gastroparesis Clinical Research Consortium have provided important concepts on gastroparesis and related disorders over the past decade. The main goal of the NIH funding of this gastroparesis consortium is to help improve the understanding of gastroparesis and care of patients by identifying the clinical and demographic profile, long term outcomes, diagnostic testing and treatment options so that the economic and quality of life burden in this patients can be improved. The main symptoms of gastroparesis: nausea, vomiting, early satiety, abdominal pain; each can impair quality of life. Symptoms mimicking gastroparesis also can occur in patients with normal gastric emptying. Gastric emptying scintigraphy used for the diagnosis of gastroparesis can reveal more on pathophysiology in gastroparesis than just global gastric emptying. These abnormalities may relate to specific symptoms. Treatments may target underlying pathophysiology as well as specific symptoms. The NIH GpCRC continues to study gastroparesis, now using its third gastroparesis registry and performing its fourth treatment trial. The GpCRC continues to gain valuable information about the disorder of gastroparesis and related conditions: pathophysiology, causes of symptoms, as well as the treatments for this often disabling disorder.

Acknowledgments

This chapter was adapted from the lecture at the ANMS 2019 Postgraduate Course, entitled “Update on Mechanisms from the Gastroparesis Consortium”.